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Hepatic artery embolization and chemoembolization of liver tumors
Hepatocellular carcinoma (HCC) is the most common primary liver cancer worldwide (see Chapter 89 ). Despite the widespread implementation of surveillance programs of high-risk populations, only 20% to 30% of HCC patients are candidates for potentially curative surgical treatment, including hepatic resection (see Chapter 101 ) and liver transplantation (see Chapters 105 and 108 ) due to poor liver function, underlying portal hypertension, tumor extent, comorbidities, and other factors. Moreover, even among those patients who ultimately undergo surgical intervention, long-term disease recurrence remains common, with reported rates ranging from 50% to 70% within 5 years. As a result—and in the absence of highly effective systemic therapies—transarterial liver-directed therapies have assumed a central role in the management of patients with malignant liver disease. Transarterial chemoembolization (TACE) has been the most commonly used intervention to achieve liver tumor control and prolong patient survival. TACE should be distinguished from hepatic artery embolization (HAE), wherein embolic material is delivered without a chemotherapeutic agent, and hepatic arterial infusion (HAI) chemotherapy, which involves the administration of one or more intraarterial antineoplastic agents without an associated embolic component.
Basic principles of hepatic arterial embolization therapy
Blood supply of liver tumors
The liver’s unique dual blood supply provides the rationale for arterially directed therapies for liver malignancies (see Chapter 2 ). Under normal physiologic conditions, the portal vein is estimated to supply approximately 70% to 80% of the normal hepatic blood flow, with the hepatic artery contributing only a minority to parenchymal perfusion. Liver tumors, however, invert this normal arteriovenous ratio and preferentially parasitize hepatic arterial inflow as the dominant source of perfusion, deriving up to 90% to 100% of flow from the hepatic arterial circulation. Directed endovascular occlusion of tumoral arterioles within the liver, therefore, may selectively induce ischemia within the tumor microenvironment while sparing nontumorous liver parenchyma supplied primarily by the portal vein. Similarly, directed intraarterial chemotherapy infusion leverages this principle to allow for significantly higher concentrations of drug delivery, with an estimated twofold to tenfold increase in the tumor for chemotherapeutic agents such as doxorubicin, cisplatin, mitomycin C, and 5-fluorouracil (5-FU) when compared with conventional systemic intravenous administration methods.
These vascular relationships are not without exception, however, as hepatocarcinogenesis is a complex and multistep process associated with differential arterialization of tumoral blood supply according to the stage of the tumor development (see Chapters 9B and 9C ). Whereas encapsulated nodular HCC, for example, commonly demonstrates near-complete supply via the hepatic artery, well-differentiated HCC as well as the extracapsular infiltrating edge of advanced HCC can be supplied all or in part by the portal vein. Similar observations have been made with liver metastases, wherein small lesions—generally less than 200 μm—are supplied almost exclusively by sinusoidal blood while larger lesions undergo progressive arterialization. However, even in an advanced stage, most liver metastases still have a discrete portal blood supply. Accordingly, both early- and late-stage liver metastases may demonstrate a higher propensity toward incomplete response to any hepatic arterial embolization therapy due to differential perfusion from both arterial and portal venous sources.
Transarterial chemoembolization
The theoretical goal of TACE is to combine the effects of targeted tumor ischemia by embolization with the antineoplastic effects of high-dose intraarterial chemotherapy. To date, there is no consensus on the optimal chemotherapeutic agent or dosing regimen, and the utility of incorporating any chemotherapeutic agent into intraarterial embolization therapy remains fundamentally unproven despite decades of research (see “Hepatic Artery Embolization” later in this chapter). Nevertheless TACE remains widely performed worldwide, and the most commonly used antineoplastic drug is doxorubicin, followed by cisplatin, epirubicin, mitoxantrone, and mitomycin C. Using a traditional (or “conventional”) approach to TACE, the chemotherapeutic drug is dissolved in water or a water-soluble contrast agent. The drug is then mixed with ethiodized oil and administered as a water-in-oil–type emulsion ( Fig. 94A.1 ). The pharmacokinetics of the resultant chemotherapy-ethiodized oil emulsions depend substantially on their composition, with greater oil-to-aqueous phase ratios exhibiting superior physical stability and sustained drug release.
When injected into the hepatic artery, ethiodized oil is preferentially accumulated in the tumor via mechanisms that are presently incompletely understood. When intratumoral sinusoids are fully occluded, additional instilled ethiodized oil may flow retrograde into the portal vein via arterioportal communications. This phenomenon allows for transient dual (arterial and portal) embolization of HCC, which may be clinically relevant when attempting to treat extracapsular infiltrative tumors and satellite nodules that are perfused via portal venules ( Fig. 94A.2 ). Once accumulated in tumor vasculature, prolonged retention of ethiodized oil is commonly observed, which may reflect the absence of lymphatics and Kupfer cells within the tumor microenvironment. In contrast, in the normal liver parenchyma, ethiodized oil is nonocclusive and accumulates in the terminal portal venules by way of the peribiliary plexus, passing into the systemic circulation via hepatic sinusoids.
After infusion of the ethiodized oil emulsion during conventional TACE, distal tumor-feeding hepatic arteries and arterioles are embolized. Hepatic artery embolization induces tumoral ischemic necrosis and increases chemotherapeutic drug dwelling time in the tumor by slowing the rate of efflux from the hepatic circulation. Furthermore, ischemic damage by embolization potentiates absorption of chemotherapeutic drugs, disrupting the function of transmembrane pumps in tumor cells. Proximal arterial occlusion should be avoided as it is associated with the development of collateral pathways of intrahepatic and tumoral perfusion, thereby limiting treatment effects, and may preclude repeat sessions of embolization therapy.
Optimal treatment effects are achieved when the appropriate size of particle embolic is selected. Although distal small particle embolization is known to improve outcomes relative to proximal and large particle treatments, the administration of excessively small particle embolic (especially in tumors with shunts) may be associated with increased risk of toxicity, including hepatic parenchymal infarction, biliary necrosis, and arteriovenous shunting to the lungs or systemic circulation.
Historically, gelatin sponge particles have been the most frequently used agent for embolization during TACE. These particles demonstrate a broad and heterogeneous distribution of sizes—some particles measuring up 1000 μm and beyond—which generally yield a more proximal embolization. As a pseudo-temporary agent, complete or partial recanalization is known to occur following gelatin sponge embolization over the course of weeks to months. Gelatin sponge has not been associated with significant hepatic parenchymal injury among patients with good hepatic functional reserve, presumably reflective of the larger particle size thereby precluding significant distal small vessel embolization.
Like gelatin sponge, polyvinyl alcohol (PVA) particles are also irregular in shape but have greater size calibration and are more permanent in nature. PVA induces permanent or semipermanent arterial occlusion and can achieve more distal embolization because of the particles’ smaller size (as low as 50–250 μm in diameter). The utilization of calibrated trisacryl gelatin microspheres has more recently come into favor, with the added advantage over other embolic agents of greater precision, in terms of both particle size distribution and particle shape. To date, however, no differences in patient outcomes have been demonstrated following treatment with TACE using different embolic materials, and thus the choice of agent remains largely a reflection of operator preference.
To prevent pulmonary and/or systemic particle embolization during TACE, attention should be paid to the presence or absence of significant arteriovenous and arterioportal shunts. Shunts are associated with larger tumors and may preclude safe administration of TACE therapy. Among patients with significant shunting, large particle embolization is recommended before chemoembolic administration, which may be delayed for up to 1 month to allow for flow redistribution following shunt closure. In cases where particle embolization is not feasible or not effective, the use of sorafenib therapy has been described as an adjunct method for shunt reduction. In rare cases, arterioportal shunt can be sufficiently large resulting in hepatofugal portal flow with ascites and variceal bleeding. In these patients, hepatopetal flow may be restored with shunt embolization, with consequent improved performance status and ascites.
Indications
The most common indication of TACE is unresectable (and noneligible for ablation) HCC (see Chapter 89 ). The determination of resectability of HCC should be based on the extent of tumor involvement and underlying liver function. Most patients with HCC have baseline liver cirrhosis (see Chapter 74 ). Compared with patients without underlying liver disease, cirrhotic patients often require a larger liver remnant after surgery to maintain adequate liver function (see Chapter 102 ). Accordingly, significantly fewer patients with cirrhosis meet criteria for potentially curative resection when compared with noncirrhotic patients. Patients with poor liver function may not tolerate extensive arterial embolization because their livers are more dependent on arterial blood supply than normal livers. Moreover, patients with severe cirrhosis are more likely to die of underlying liver disease than of HCC. Thus TACE is typically recommended in patients with reasonably preserved liver function (Child-Pugh class A or B7) and performance status (Eastern Cooperative Oncology Group [ECOG] score 0 or 1).
Several methods have been proposed to provide a clinical classification of HCC, including the French classification, the Cancer of the Liver Italian Program (CLIP), the Chinese University Prognostic index (CUPI), and the Japan Integrated Staging (JIS) staging systems (see Chapter 89 ). However, these staging systems for predicting prognosis of patients with HCC do not indicate which patients would benefit from TACE. In 2002 the Barcelona Clinic Liver Cancer (BCLC) staging system was developed and subsequently endorsed by both the European Association of the Study of the Liver (EASL) and the American Association of Study of Liver Diseases (AASLD). , According to the BCLC staging system, TACE is recommended as first-line therapy for intermediate-stage HCC, defined as multinodular disease without macroscopic vascular invasion or extrahepatic spread among patients with favorable performance status. However, less than 15% of the patients with HCC initially present with this stage, and in clinical practice TACE is commonly also employed for patients with early-stage (although larger in size) HCC by BCLC criteria. Recent guidelines for HCC management reported that TACE is the most frequently used first treatment for HCC in Asia and North America.
Spontaneous rupture of HCC is an indication for embolization-based intervention, regardless of underlying liver function (see Chapter 31 ). Even in patients with advanced liver cirrhosis, nodular HCC showing exophytic growth can be managed safely by selective embolization to prevent tumor rupture without deterioration of liver function.
TACE with or without thermal ablation techniques may play a neoadjuvant role as a downstaging therapy before resection or as a bridge therapy for patients awaiting liver transplantation. Data are conflicting, however, with early reports demonstrating no improvement in overall survival following pretransplant TACE, as well as no change in transplant list dropout rates. As methodologically sound prospective data are lacking to definitively guide decision making, the use of TACE for these indications remains unproven (see Chapters 101B and 108A ).
Beyond primary hepatic malignancy, patients with metastatic liver disease may also benefit from TACE, including patients with neuroendocrine tumors (NETs) (see Chapter 91 ), gastrointestinal stromal tumors (GISTs), uveal melanoma (see Chapter 92 ), and other common pathology, including primary breast and lung cancers. The most common indications are rapid progression of liver tumor with stable or absent extrahepatic disease and symptoms related to tumor bulk or hormonal excess, especially among patients with NET. In addition, there has been growing interest in the application of liver-directed therapies such as TACE in the setting of liver-isolated or liver-dominant oligometastatic disease with the goal of generating a prolongation of chemotherapy-free survival.
Generally accepted contraindications to therapy with TACE include patients with decompensated cirrhosis (Child-Pugh B8 or higher) (see Chapter 4 ) and extensive tumor with massive replacement of both lobes of the liver. Major portal vein invasion has traditionally been considered a contraindication to TACE, but this can be safely and effectively managed by an adjustment of the embolization protocol to reduce the amount of chemoembolic agents and the extent of the embolization, especially in patients with a limited parenchymal tumor and adequate liver function , ( Fig. 94A.3 ). In addition, active gastrointestinal bleeding, refractory ascites, extrahepatic spread, hepatic encephalopathy, biliary obstruction, documented history of severe allergic reaction to contrast media, and uncorrectable coagulopathy are also considered contraindications to TACE.
Procedure
Before the TACE procedure, comprehensive laboratory testing should be performed, including complete blood cell count, prothrombin time with international normalized ratio, creatinine levels, and liver synthetic function assessment. Baseline tumor markers, where appropriate, should be measured to monitor for changes after treatment. Contrast-enhanced cross-sectional imaging of the liver (multiphase computed tomography [CT] or magnetic resonance imaging [MRI]) should be performed to evaluate the number, size, and segmental location of the tumors, their growth pattern (expansible vs. replacing or infiltrating), and the presence or absence of macroscopic vascular invasion into the hepatic or portal venous systems. In addition, imaging of the chest, abdomen, and pelvis is recommended to document the presence or absence of metastatic disease. Patients are to remain nil per os overnight before the procedure and are kept hydrated with continuous intravenous infusion of crystalloid before, during, and following embolization. Antiemetics and narcotic analgesics are administered intravenously, and patients with documented contrast allergies may receive oral steroids and/or antihistamine therapy before the procedure.
The use of antibiotic prophylaxis before and after embolization has historically been recommended among patients undergoing hepatic embolization therapy, particularly among patients with a biliary enteric anastomosis or prior biliary instrumentation. More recent literature suggests that, among patients with an intact sphincter of Oddi, the elimination of postprocedure antibiotics does not adversely affect outcomes among patients with primary and secondary liver tumors receiving embolization-based therapies. This practice is supported in the most recent guidelines on antibiotic prophylaxis published by the Society of Interventional Radiology.
After local administration of anesthetic solution, the Seldinger technique is used to gain access to the common femoral, radial, or other target artery, and initial diagnostic visceral arteriography is performed to determine arterial anatomy of the liver and patency of the portal vein. Anatomic variations of celiac trunk and hepatic arteries are frequently encountered, with common variants including the right hepatic artery arising from the superior mesenteric artery and the left hepatic artery arising from the left gastric artery. For complete angiography, all hepatic arteries should be adequately opacified by selecting an appropriate catheter as well as a corresponding rate and volume of contrast injection. All tumor-feeding arteries should be identified; selective segmental or subsegmental hepatic arteriograms with multiple oblique angles and magnifications are frequently necessary to identify small tumor-feeding arteries. In addition, cone beam computed tomography (CBCT) and CT arteriography have shown particular value in identifying tumoral vascular supply and are robust problem-solving tools for challenging cases due to the ability to visualize tumor-vessel relationships as a volumetric rendering. Data from a systematic review and meta-analysis of CBCT performed during TACE for HCC demonstrated a sensitivity for tumor detection of 90% relative to 67% with conventional angiography. Similarly, CBCT demonstrated a sensitivity for detection of tumor feeding arteries in 93% of cases compared with 55% using digital subtraction angiography alone.
The treatment protocol should be individualized according to the patient’s liver function, extent of tumor, presence or absence of macroscopic vascular invasion, and the patient’s baseline functional status. Every effort should be made to preserve nontumorous liver parenchyma from ischemia and cytotoxicity induced by embolization and chemotherapeutic administration, respectively. Selective or superselective administration of chemoembolic has been shown to provide the broadest safety margin, sparing uninvolved liver parenchyma while improving treatment outcomes from TACE, particularly when treating lesions with one or two vascular pedicles that can be targeted selectively.
After an appropriately sized microcatheter is positioned selectively into the tumor-feeding artery in close proximity to the tumor, the ethiodized oil-chemotherapy emulsion is injected. If significant arteriovenous shunting is present, large-particle (300–500 μm) embolization may be used to reduce the risk of passage of the chemoembolic emulsion into the systemic circulation. This can decrease the risks of complications such as oil pulmonary embolism, pneumonitis, paradoxic cerebral ischemia, or systemic toxicity from the distribution of the chemotherapeutic agent.
The amount of oil-chemotherapy emulsion to be injected depends on the size and vascularity of the tumor. The dose of doxorubicin typically ranges from 20 to 75 mg, with a maximum prescribed dose of 150 mg. The generally accepted upper limit of volume for ethiodized oil is 15 mL; however, safe administration of volumes up to or even exceeding 40 mL have been described in patients with large HCC tumor burden. For a small- or medium-sized tumor, sufficient ethiodized oil is injected to saturate the tumor neovasculature and to partially opacify portal venules. The end points for the emulsion administration are stasis in tumor-feeding arteries and/or appearance of ethiodized oil in portal vein branches ( Fig. 94A.4 ). After infusion of the emulsion, tumor-feeding hepatic arteries are embolized with the use of gelatin sponge, PVA particles, or other embolic material.
Embolization of extrahepatic collaterals supplying the tumors is crucial to achieve successful outcomes. When a tumor is adjacent to a hepatic bare area or suspensory ligaments, for example, or it invades into an adjacent organ, a selective arteriogram of possible extrahepatic arteries should be obtained. With recent advances in imaging technology, collateral vessels can often be identified by thorough review of preprocedure CT data performed in the arterial phase. Common extrahepatic collaterals include the inferior phrenic artery, omental artery, internal mammary artery, colic branch of superior mesenteric artery, adrenal artery, intercostal artery, renal capsular artery, and gastric arteries ( Figs. 94A.5 and 94A.6 ). When the hepatic artery and extrahepatic collaterals supply the tumor, additional TACE or particle embolization of the extrahepatic collaterals should be performed—if deemed safe—in an effort to optimize therapeutic efficacy. These extrahepatic collaterals can also be used as an access route to the tumors in patients with hepatic artery occlusion, an event that can occur in patients who undergo multiple prior TACE or other intraarterial therapies.
Recently, the use of CBCT has assumed a central role in intraprocedural imaging. This technology can provide greater detail regarding relevant vascular anatomy and associated liver parenchyma beyond that provided by conventional digital-subtraction angiography (DSA) and fluoroscopy. CBCT allows the operator to recognize tumor-feeding vessels with greater confidence, which may in turn allow for more selective administration of chemoembolic material and thereby decrease the volume of nontumoral liver parenchyma within the treatment zone ( Fig. 94A.7 ). Moreover, CBCT aids in the identification of important extrahepatic arteries, including the supraduodenal and retroduodenal arteries, right gastric artery, phrenic artery, and falciform artery, which may serve as sources of nontarget embolization. The relative contribution of individual feeding arteries to tumoral perfusion may also be assessed using CBCT, allowing for more accurate apportionment of chemoembolic material during treatment. Last, as ethiodized oil is intrinsically radiodense, CBCT as well as CT (in hybrid rooms capable of both angiographic and diagnostic helical CT) can be performed following the TACE procedure without injection of additional iodinated contrast media, and the completeness of embolization can be assessed according to the percentage of tumor volume demonstrating retention of the administered oil emulsion. If incomplete coverage of the target lesion(s) is identified, additional angiographic imaging can then be performed before completion of the TACE procedure to identify other sources of hepatic or extrahepatic tumor supply that may require treatment. ,
After the procedure, intravenous hydration is continued, and analgesic and antiemetic medications are supplied on an as-needed basis. Patients can be discharged once they have resumed adequate oral intake and intravenous analgesics are no longer required, which may occur on the day of the procedure or following a short inpatient hospital stay, typically 1 to 2 days in duration. Laboratory studies of liver function and tumor markers (where appropriate) should be repeated 2 to 4 weeks after the procedure. Multiphase contrast-enhanced CT or MRI is recommended every 2 to 3 months after the procedure to evaluate the efficacy of the treatment and to detect local or distant tumor recurrences. When there is residual/recurrent tumor on follow-up imaging or elevation of tumor markers, patients may return for another session of TACE according to their hepatic functional recovery.
No consensus has been reached on the ideal protocol for repeat TACE, but the additional embolization is generally recommended only when progression of disease is documented radiographically (“on-demand” strategy). , Among patients without objective response after two treatments, additional TACE procedures should not be performed. Similarly, caution should be exercised in patients who develop clinical or functional deterioration (ECOG performance status greater than 2 or hepatic decompensation) after their initial TACE procedures.
Therapeutic efficacy of chemoembolization
Hepatocellular carcinoma (see Chapter 89 )
Numerous studies have shown that TACE induces significant tumor necrosis without negative influence on liver function in selected patients with sufficient hepatic synthetic reserve. The extent of tumor necrosis has been reported to range from 60% to 100%, with higher rates reported among patients treated using selective or superselective chemoembolic administration. In comparison with lobar TACE, selective TACE led to significantly higher rates of mean necrosis (75.1% vs. 52.8%) and complete necrosis (53.8% vs. 29.8%). , Miyayama et al. treated 123 HCCs smaller than 5 cm using a 2-Fr microcatheter and reported local recurrence rates of 25.6% and 34.7% at 1 year and 3 years, respectively. The rate of local recurrence was significantly lower when a greater degree of portal vein visualization was demonstrated during TACE. However, in large tumors, even though necrosis may appear macroscopically complete, histologic examination often reveals foci of residual viable tumor cells, which may reestablish vascularity and resume growth during the early or late follow-up interval, thereby accounting for the known high rates of recurrence after TACE therapy. Several studies have suggested that tumor characteristics lead to a favorable response after TACE, including small, encapsulated, expansile, hypervascular tumors. , Pathologically, trabecular-type HCC showed more prominent necrosis than scirrhous, compact, or well-differentiated HCC.
The survival benefit associated with TACE has been demonstrated by two randomized controlled trials (RCTs). The first, performed in 2002, demonstrated significantly prolonged overall survival among 40 patients treated with TACE using gelatin sponge and doxorubicin when compared with 35 patients treated with conservative medical therapy alone. This study was pivotal for the establishment of TACE as standard of care therapy of intermediate stage nonresectable HCC. The same study included a third arm—embolization alone using proximally administered gelatin sponge without the administration of intraarterial doxorubin or ethiodized oil—that enrolled 37 patients. Though widely cited as evidence of the superiority of TACE over embolization alone, the trial was ended prematurely following the ninth interim analysis after a survival benefit of TACE was demonstrated relative to the control arm that received medical therapy alone, whereas no survival benefit was demonstrated over those treated with embolization alone. Additionally, two patients within the embolization arm did not receive the embolization procedure but were included based on the intention-to-treat methods of the trial. Accordingly, no conclusions about the relative efficacy of TACE over embolization alone can be drawn from this trial.
A second trial—also published in 2002—compared standard medical therapy alone to TACE performed using gelatin sponge, ethiodized oil, and cisplatin among 80 patients with unresectable HCC evenly randomized between two treatment groups. Survival was significantly prolonged in the TACE group, though the rate of death from liver failure was also significantly increased.
As a result of these investigations, TACE became established as the standard of care for patients who meet the criteria for BCLC intermediate stage HCC. Llovet et al. , showed that median and 3-year survival rates were 19 to 20 months and 29%, respectively, in BCLC intermediate-stage patients. In 2010 a retrospective study reported that the overall median time-to-progression (TTP) was 7.9 months, and median survivals of patients in stages A, B, and C of the BCLC staging system were 40.0, 17.4, and 6.3 months, respectively. However, TTP is not a validated surrogate for overall survival in hepatocellular carcinoma, and thus the significance of these latter findings is uncertain.
Geographic disparities in the utilization of TACE preclude direct comparison of outcomes in differing populations. The 4966 patients stratified to TACE recommended by the Japanese guidelines showed that 3-year survival of patients with two or three tumors greater than 3 cm or four or more tumors was 55% and 46% in Child-Pugh class A, respectively, and 30% and 22% in class B, respectively. In a study from Japan and Korea, the 2-year survival rate of 99 patients with unresectable HCC was 75.0%. The median TTP was 7.8 months, and the median overall survival period was 3.1 years.
TACE as a neoadjuvant therapy in candidates for hepatic resection is controversial. Several early studies reported a possible survival benefit in patients treated with TACE before resection of HCC when compared with resection alone. , However, in two subsequent randomized trials, , preoperative TACE did not improve surgical outcomes, including postoperative recurrence, disease-free survival rates, and overall survival rates. Moreover, the preoperative TACE group had a lower resection rate and longer operative time, thus evaporating enthusiasm for this therapeutic approach.
Liver transplantation (LT) is associated with the best prognosis among patients with early-stage HCC associated with underlying liver cirrhosis (see Chapter 115 A). However, because of a steadily increasing waiting time, a substantial proportion of patients are excluded from LT secondary to tumor progression. The cumulative probability of dropout from the waiting list has been reported to range from 7% to 11% at 6 months up to 38% at 12 months following listing for LT. The impact of TACE as a bridge therapy before LT is still uncertain due to absence of controlled studies comparing patients who underwent LT with and without neoadjuvant TACE. The most recent series, including patients treated with TACE before LT, have indicated that the dropout rate due to tumor progression may be lower and ranges between 3.0% and 9.3%, with a mean waiting time on the transplantation list exceeding 6 months.
A recurrence rate of less than 15% has been reported in patients within the Milan criteria undergoing LT without preceding neoadjuvant therapies. , Whether receiving TACE while on the waiting list decreases this rate is still controversial. Two large studies reported low recurrence rates of 7.6% and 10.7% in patients who were treated with TACE before LT. , However, in a case-control study that included 100 patients who received pretransplant TACE and 100 control patients, pretransplant TACE was not an independent predictor of posttransplantation survival or disease-free survival. More recently, Tsochatzis et al. evaluated 150 consecutive patients and reported significantly lower HCC recurrence after LT in the TACE group (6%) than in the control group (18.1%). No prospective randomized trials have been performed to evaluate the effects of TACE on post-LT recurrence.
TACE has also be employed to downstage patients with advanced HCC and thereby expand selection criteria for LT. However, due to the wide heterogeneity of published techniques—including combination therapies—the true effect of this approach on patient outcomes remains unknown (see Chapter 108A ). Estimated rates of successful downstaging range from 24% to 71%, and the proportion of patients successfully transplanted ranges from 10% to 67%. The reported survival rates range from 78.8% to 100% and from 54.6% to 93.8% at 3 and 5 years, respectively. Two prospective studies have demonstrated that survival after LT in patients with large tumors successfully downstaged is similar to that of patients who initially met the criteria for LT. ,
Neuroendocrine tumors (see Chapter 91 )
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) collectively represent the second most common gastrointestinal malignancies after colorectal cancer. The World Health Organization classifies GEP-NETs into grade 1 (G1), grade 2 (G2), and grade 3 (G3) carcinoma, formerly called carcinoid, well-differentiated, and poorly differentiated tumors, respectively. GEP-NETs are metastatic at the time of initial diagnosis in 21%, 30%, and 50% for G1, G2, and G3 tumors, respectively, and may develop in up to 90% of patients over the course of their disease. Tumor grade and metastatic status represent the most important prognostic factors. In general, G1 and G2 tumors are considered potential candidates for locoregional therapies, whereas G3 tumors generally are only candidates for systemic treatment due to rapid progression and widespread metastasis. The development of liver metastasis may induce the systemic release of hormonal agents and invoke symptoms such as rash, hypertension, diarrhea, and electrolyte disorders; these are collectively known as carcinoid syndrome. In the later stages of the disease, significant hepatomegaly caused by bulky metastatic tumors may result in progressive pain and dyspnea, and the primary goal of hepatic embolization therapy is to reduce liver tumor burden and palliate symptoms.
TACE is one therapeutic locoregional therapeutic option for patients with liver metastases from GEP-NET. Symptomatic response is obtained in 52% to 86%; the response is even higher when TACE is used as a first-line therapy, with 70% complete symptomatic response and 20% partial response. In a retrospective study by Hur et al., a median overall survival of 38.6 months was demonstrated (55 months for nonpancreatic NET and 27.6 months for pancreatic NET). In the absence of randomized trials evaluating locoregional therapies, no definitive answers to factors influencing outcomes of treatment can be provided. However, from retrospective series, outcomes are inversely related to the degree of liver replacement by tumor, and after embolization therapy, patients with nonpancreatic NET have significantly prolonged survival compared with patients with pancreatic NET. When employed early in the disease course, TACE is associated with favorable results—including symptom control—and published 5- and 10-year overall survival rates of 83% and 56%, respectively, when used in first-line therapy. ,
High tumor burden—variably quoted as greater than 50% or 75% tumoral involvement—has previously been associated with poor outcomes. In this high-risk population, embolization therapy should be performed in stages, typically as sequential lobar treatments ( Fig. 94A.8 ). For small tumors and for patients with fewer than three tumors, hepatic embolization therapy can be combined with local ablation therapies to maximize tumor necrosis and improve local disease control. Before the introduction of pharmacologic antagonists of tumor metabolites, exacerbation of the symptoms of carcinoid or carcinoid crisis was common after embolization therapy. The increased availability of somatostatin analogs has resulted in a significant reduction of this complication after embolization therapy.
Despite these encouraging reports of success with TACE for treatment of metastatic NET, the potential for long-term morbidity remains a concern. Patients with metastatic NET—particularly those with low-grade histology—may experience prolonged survival by undergoing repeated locoregional liver-directed therapies, and hepatic dysfunction can accrue following multiple such interventions. Accordingly, the United States National Comprehensive Cancer Network (NCCN) treatment guidelines currently recommend against the use of TACE using drug-eluting bead (DEB) technology in this patient population due to higher reported rates of toxicity when compared with conventional TACE with ethiodized oil or transarterial embolization alone.
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