THERE IS A GREAT ROLE OF TACE PROCEDURE FOR LIVER CANCER, IT CAN BE THE MOST EFFECTIVE AND TIME SAVING FOR HCC CASES.
Primary and secondary liver tumors are a common cause of morbidity and
mortality around the world. While curative therapies for some of these cancers
exist – hepatocellular carcinoma (HCC) can be treated with partial hepatectomy
or liver transplantation – many patients are ineligible for curative liver resection
due to the advanced stage of their cancers; furthermore, widespread implementation of liver transplantation is prevented by a shortage of donor organs.
The same is true for patients with metastatic colorectal or neuroendocrine tumors. Due to these
shortcomings, various palliative therapies have been advanced in the management
of hepatic neoplasms.
These include systemic chemotherapy, radiation therapy, and local and regional percutaneous modalities. The latter group comprises both ablative techniques (chemical and thermal), and the intra-arterial monotherapies.
Unlike healthy hepatocytes, which are supplied largely by the portal venous circulation, both primary and secondary liver tumors receive their vascular supply principally from the hepatic artery.
Thus, occlusion of the hepatic artery would be expected to lead to ischemic necrosis of tumor cells while selectively sparing the native liver. This principle has been exploited in the development of bland transarterial embolization (TAE) and transarterial chemoembolization (TACE).
In both of these approaches, the branches of the hepatic artery that supplies the tumor are occluded with embolic particles.
For chemoembolization, chemotherapeutic agents are added to the embolization mixture for delivery directly into the tumor.
In principle, chemoembolization targets liver lesions by a multifaceted attack. First, embolization of the vascular supply triggers localized tissue ischemia. Second, since the chemotherapeutic agents are delivered directly into the ischemic tumor, their local concentrations and tissue dwell times can be significantly increased [1–5].
Equally importantly, the ischemia induced by chemoembolization may counteract
drug resistance by causing metabolically active cell membrane pumps to fail, thereby
increasing intracellular retention of the chemotherapeutic agents [3,6].
Technique of chemoembolization
Preoperative evaluation for chemoembolization includes imaging, serology, and counseling. A patient should have either a definitive tissue diagnosis or a compelling clinical diagnosis, such as a markedly elevated serum alpha-fetoprotein (AFP) level associated with an HCC-like mass in a cirrhotic liver .
The patient must have a dynamic gadolinium-enhanced MRI or triple-phase CT of the liver.
The extrahepatic disease should be excluded by a bone scan and cross-sectional imaging of the chest, abdomen, and pelvis. Serological studies should include CBC, PT,
PTT, creatinine, liver function tests, and AFP levels. Due to the demanding nature
of this palliative treatment, patients should receive thorough counseling about
their regimens. In particular, this discussion should mention the common postembolization syndrome, the 5–7% risk of serious complications, and the 1–4%
chance of periprocedural mortality. The patient and family members should clearly
understand that chemoembolization is a palliative regimen with the potential for
significant discomfort, risk, and expense.
Patients need not be routinely admitted until the morning of their procedure, but they should be advised to fast overnight.
On the morning of the procedure, patients are hydrated with 0.9% NSS at 200–300 cm3 h−1. Prophylactic medications are administered intravenously, including antibiotics (cefazolin 1 g, metronidazole 500 mg) and antiemetics (odansetron 24 mg, decadron 10 mg, diphenhydramine
The evidence for antibiotic prophylaxis is not compelling except for patients without a functioning sphincter of Oddi (e.g., post-Whipple or biliary stent), and not all practitioners administer them routinely.
The patient is sedated, prepped, and draped. Before any embolization is performed, diagnostic angiography of the celiac and superior mesenteric arteries is performed to determine the arterial supply to the liver and to confirm the patency of the portal vein.
Because non-target embolization of the gut or gallbladder is a significant cause of morbidity, the origins of the right gastric, supraduodenal, cystic, and other potential extrahepatic arteries must be clearly identified .
Once the arterial anatomy has been mapped, a catheter is advanced super selectively into a lobar or segmental branch of the right or left hepatic artery.
Typically, the lobe with the greatest tumor burden is embolized first, with subsequent treatments
targeting the contralateral side.
The chemo-embolic mixture is injected into the segmental artery until nearly complete stasis of blood flow is achieved. Intra-arterial lidocaine (30mg boluses, up to a total of 200mg) and intravenous fentanyl and midazolam should be used to alleviate discomfort during the procedure
Antibiotics, antiemetics, and intravenous hydration are continued after the embolization (3L of 0.9% NSS over 24h).
The common post-embolization syndrome must be managed aggressively with palliation of pain, nausea, and fever.
Specifically, narcotics, perchlorpromazine, odansetron, decadron, and acetaminophen should
be liberally administered.
The patient can be discharged with the resumption of oral intake and the cessation of parenteral narcotic therapy.
Typically, half of the patients are discharged on the first postoperative day, while most of the remainder leave after 2 days .
Oral home medications include antibiotics (5 days), antiemetics, and narcotics when needed. Laboratory studies are repeated in 3 weeks to ensure the normalization of liver enzymes. Depending upon the tumor burden and arterial anatomy, a cycle of chemoembolization will include between one and four procedures. Thus, the patient will return for the next embolization in about 4 weeks; treatments alternate between the left and right lobes, as well as any parasitized
Following completion of the treatment cycle, responseis assessed with repeat cross-sectional imaging and tumor marker serology. If the response has been inadequate, further rounds of chemoembolization can be administered.
Choice of embolic particles
Variousembolicparticlesareavailableon the market.Thoughtheydifferinstructure, no agent has been conclusively demonstrated to be superior to any other.
The first embolic particle to be developed, the gelatin sponge (Gelfoam; Upjohn, Kalamazoo,
MI) has been used in the majority (71%) of chemoembolization trials .
Historically it has been available in various formulations – particles, cubes, pellet, powder,
fragments, and strips – the size of the particles determining how distal the embolization would take place .
Notably, use of the powder formulation has been discontinued because of an unfavorable side-effect profile. In all of these formulations, the gelatin causes only temporary devascularization, allowing recanalization to take place in about 2 weeks.
A similar temporary occlusion agent has also been developed from cross-linked bovine collagen (Angiostat; Regional Therapeutics, Pacific Palisades, CA).
More permanent embolic particles include polyvinyl alcohol (PVA; several vendors) and trisacryl gelatin spheres (Embosphere microspheres; BioSphere Medical, Rockland, MA).
Both of these come in a range of sizes (40–1000 μm), allowing the clinician to select the level of embolization. Less commonly, reports exist of the use of steel coils, starch microspheres, autologous blood clots, and even the herb Bletilla striata to embolize the hepatic artery . Recent studies have begun to assess the feasibility of drug-eluting beads, a new approach that may
offer an improved pharmacokinetic profile compared to traditional chemoembolization .
Choice of chemotherapeutic agents
Several chemotherapeutic agents are available for chemoembolization, for use as monotherapy or in combination.
Doxorubicin and cisplatin are the most commonly used single agents . Most reports from Europe and Asia use doxorubicin or epirubicin, whether alone or in combination with mitomycin-C.
Centers in the United States prefer cisplatin monotherapy or a combination of 100–150 mg
cisplatin, 40–60 mg doxorubicin, and 10–20 mg of mitomycin-C (CAM).
Although at least one case series suggested that cisplatin may confer a survival benefit over doxorubicin , no randomized trial has shown the superiority of any of these agents .
In fact, apparent differences between these agents may be driven by the ability to administer more embolizations in patients treated with cisplatin .In any case, no clear consensus has yet emerged for the superiority of any chemotherapeutic agent or combination.
Choice of emulsion: transarterial oily chemoembolization
The observation that iodized poppyseed oil (Ethiodol; Savage Laboratories, Melville, NY) selectively accumulated in hepatocellular carcinomas led to the incorporation of lipiodol (Guerbet, Aulnay-sous-Bois, France) into chemo-embolic regimens.
This technique, now known as transarterial oily chemoembolization, has the potential to more accurately target the chemotherapeutic drugs.
When iodized oil is injected into the hepatic artery, it travels to the distal arterioles, where it shunts
into the terminal portal venules at the pre-sinusoidal level.
From there, the oil slowly moves into the sinusoids and becomes trapped in the tumor vessels. In
theory, any chemotherapeutic agents suspended in this oily phase would thus be targeted to the liver.
Studies in rabbits  and humans  have demonstrated that the combination of oily chemoembolization with a particulate agent is superior to oily chemoembolization alone .
Such an effect is probably caused by the fact that most chemotherapeutic drugs remain in the aqueous phase of the emulsion. When chemoembolization is performed exclusively with an oily emulsion, continuous arterial inflow elutes out the aqueous drug, even though the oil itself remains
suspended in the liver.
Particulate-only chemoembolization causes relatively proximal occlusion, allowing continued inflow into the tumor from the portal venules, again diluting the chemotherapeutic drugs and resulting in reduced ischemia.
Thus the combination of oil and particles allows the occlusion of both distal arterioles and
portal venules – effectively sandwiching the drugs and maintaining tumor ischemia. Additionally, since this technique increases hepatic drug retention, it has the benefit of reduced systemic toxicity
Efficacy of chemoembolization
Historically, the efficacy of the transarterial embolo- therapies has been somewhat controversial. For example, early studies were inconclusive about the efficacy of chemoembolization in the treatment of hepatocellular carcinoma.
Nevertheless, evidence has emerged during this decade from several randomized trials that a role
exists for chemoembolization in the management of HCC.
Though the evidence is slightly less clear for the management of colorectal and neuroendocrine metastases, chemoembolization has nonetheless become established as an important palliative
therapy in the oncologist’s armamentarium.
Role of chemoembolization in unresectable hepatocellular carcinoma
Initial retrospective cohort studies in the Orient, Europe, and the United States suggested that chemoembolization was effective in the palliation of unresectable HCC: rates of tumor necrosis ranged from 60% to 100% .
Cumulative probability of survival in these studies was 54–88% at one year, 33–64% at 2 years, and 18–51% at 3 years, with the best results obtained by repeated embolizations with a combination
of iodized oil, gelfoam, and chemotherapeutic drugs.
Survival varied directly with oil uptake and retention, and inversely with tumor volume, stage, and Child class.
Nevertheless, early randomized controlled trials failed to demonstrate a survival benefit for patients with unresectable HCC. Chemoembolization with gelfoam/doxorubicin (n = 42 patients) , lipiodol/5-epidoxorubicin (n = 50) , and gelfoam/lipiodol (n = 96)  did not increase survival compared to control subjects who received only palliation of pain.
Interestingly, however, two of these studies [13,14] did demonstrate non-significant trends towards increased survival from chemoembolization, suggesting that they may have been underpowered to
answer this question.
Since that time, however, evidence has begun to mount in favor of chemoembolization in the management of unresectable HCC. In 2002, two randomized studies demonstrated a clear survival benefit from chemoembolization.
In the first study, of 80 patients from Hong Kong, survival in patients treated with cisplatin/
lipiodol/gelatin-sponge chemoembolization was 57%, 31%, and 26% at 1, 2, and 3
years, compared with 32%, 11%, and 3% in those receiving conservative management .
In the second study, of 112 patients from Barcelona, 1-year and 2-year survival was 82% and 63% in patients receiving doxorubicin/gelatin-sponge chemoembolization, 75% and 50% in those treated only with gelatin-sponge bland TAE, and 63% and 27% for those receiving conservative management .
The authors hypothesized that the results of these trials may have differed from earlier studies because of differences in patient demographics and tumor background .
In particular, the studies from Hong Kong and Barcelona were conducted in patients whose HCC arose in the presence of viral hepatitis in 80% of cases, compared to a higher preponderance of alcohol-induced liver disease in the earlier French studies .
The tolerance of patients with alcohol-induced cirrhosis for chemoembolization may have been lower than that of those with viral hepatitis .
A recent meta-analysis of 175 cohort studies and randomized controlled trials (RCTs) of chemoembolization in the treatment of unresectable HCC concluded that chemoembolization does provide a significant survival benefit when compared to conservative therapy (631 patients in nine RCTs, p = 0.0025) .
Interestingly, a sub-analysis of studies comparing chemoembolization to bland TAE (412 patients,
3 RCTs) failed to demonstrate a survival benefit for either methodology, though
chemoembolization trended towards an improved outcome (p = 0.052).
Lastly, chronologically later studies demonstrated improved outcomes in comparison to
earlier trials ; this finding could be partially explained as a result of the improving
proficiency of clinicians.
In summary, evidence indicates that patients with unresectable hepatocellular carcinomas benefit from transarterial chemoembolization, though the benefit of specific choices of chemoembolic combinations remains unproven.
Disagreements between early randomized trials of chemoembolization and newer studies may have
resulted from differences in the patient populations or from the improving proficiency of clinicians.
Role of chemoembolization as a neoadjuvant therapy in HCC
While chemoembolization has become well established as a palliative therapy in the management of unresectable hepatocellular carcinomas, its role as a neoadjuvant therapy for HCC has been more controversial.
In theory, chemoembolization could prevent tumor growth in patients awaiting orthotopic liver transplants, thus decreasing attrition from the transplant waiting list due to tumor progression: as
such, chemoembolization could serve as a bridge to transplantation.
Alternatively, preoperative chemoembolization might be expected to improve outcomes after
partial hepatic resection, and might even convert some unresectable lesions into resectable tumors.
Early support for the role of chemoembolization as a neoadjuvant came from retrospective cohort studies showing that neoadjuvant chemoembolization could induce a reduction in tumor size and thus a downstaging of HCC before hepatic resection or liver transplantation [17,18].
Similarly, while the 6-month drop-out rate from the transplant waiting list is typically between 23% and 46% , those patients who receive neoadjuvant chemoembolization have been reported to have a drop-out rate of only 15% .
Nevertheless, while such early studies were encouraging, it is unclear whether their conclusions can translate to improved outcomes.
For example, the aforementioned study  failed to demonstrate a statistically significant improvement in patient survival, thus calling into question the clinical relevance of the findings.
In fact, the results of later retrospective cohort studies of chemoembolization as a bridge to transplant have been contradictory [19,21], and no RCT has yet been conducted on the issue.
In fact, a recent systematic evidence-based review of the available studies concluded
that at present there is insufficient evidence to claim that chemoembolization could be used as a bridge to transplant, that it would decrease transplant waiting list drop-out rates, or that preoperative chemoembolization could improve posttransplant survival in patients with HCC .
Perhaps the most relevant confounding variable is wait times for listed patients. In regions with short wait times (< 3 months), the drop-out rate is low, so neoadjuvant therapy is not
When wait times are very long, approaching the median time to-progression after image-guided therapy, the benefit from neoadjuvant stabilization is lost.
The wide geographic and temporal variation in wait times makes analysis of the benefit of neoadjuvant therapy from prior literature difficult.
Nevertheless, in the absence of any randomized trials, chemoembolization continues to be used in a non-palliative role in the pre-transplant setting, largely because it at least has not been shown to increase postoperative complications in transplant patients .
The effectiveness of preoperative chemoembolization in patients receiving hepatic resection has been similarly controversial. In theory, the combination of chemoembolization with curative surgery might be expected to improve patient outcomes.
Moreover, since chemoembolization has been shown to be capable of downstaging tumors , it might be able to convert some patients with unresectable lesions into surgical candidates. Indeed, some studies have shown just this, with preoperative chemoembolization significantly improving the 5-year survival of patients undergoing hepatic resection from 19% to 39% .
These findings have been further supported by a large retrospective cohort analysis
However, other prospective trials have failed to show a benefit from neoadjuvant chemoembolization before hepatic resection; one prospective study actually demonstrated worsened actuarial survival in chemoembolized patients due to the delay in curative resection .
A review of various adjuvant and neoadjuvant therapies in HCC has concluded that there is insufficient evidence to claim that neoadjuvant chemoembolization improves patient survival before resection .
Still, in the absence of definitive randomized controlled trials, the issue remains unresolved.
In summary, the role of chemoembolization as a neoadjuvant before liver transplantation or hepatic resection has been rather controversial.
Despite positive findings from some studies, the preponderance of evidence has not yet supported
such an indication. In fact, where the administration of chemoembolization may delay a definitive therapy, chemoembolization may actually worsen patient survival .
Clearly, randomized controlled studies are needed to further clarify these questions.
Toxicity of Chemoembolization
Despite having a more favorable side-effect profile than conventional chemotherapy, chemoembolization is not free of complications.
Thirty-day mortality ranges from 1% to 4%; chemoembolization in the treatment of HCC had a median mortality of 2.4% in a recent meta-analysis of 2858 patients .
Severe complications of chemoembolization occur in 5–7% of subjects, though these rates can be
reduced to 3–4% when patients are properly selected.
Most patients suffer from a self-limited post-embolization syndrome. Major complications of chemoembolization include hepatic insufficiency, abscesses, ischemic complications (cholecystitis,
bile duct necrosis, perforation of the alimentary tract), and renal dysfunction.
Less commonly, chemoembolization can also lead to tumor rupture, occlusion of the hepatic artery, and clinically significant pancreatitis.
The majority of patients (40–86%) [14,38] suffer from a condition termed post-embolization syndrome (PES).
This is generally characterized by fever (74% of patients), abdominal pain (45.2%), nausea/emesis (58.9%), and a transaminitis (54%) .
In most cases PES is self-limited, though its palliation does necessitate hospitalization. On average, patients defervesce within 3 days, their nausea and pain can be medically managed, and their hepatic function gradually returns to normal .
Though previously thought to be indicative of tumor necrosis and thus a successful treatment, neither the presence nor the severity of PES has been shown to correlate to positive patient outcomes .
While reliable clinical predictors of the severity of PES have not yet been identified,PES does trend towards a more indolent course when embolization of the gall bladder is avoided, and when the patient is receiving repeat embolization to previously treated territory .
Acute irreversible hepatic decompensation has been reported to occur in 3% of patients [8,39]. It should be distinguished from the transient and self-limited transaminitis that occurs with post-embolization syndrome.
Irreversible decompensation is more common with the use of high doses of cisplatin and poor
pretreatment hepatic function (high bilirubin, prolonged PT, and advanced cirrhosis) .
Abscess formation affects between 0.2% and 2.5% [40,43] of patients receiving chemoembolization.
The majority of these infections occur in the liver, though 0.4% of patients may suffer from a splenic abscess .
While their proximate cause is an infectious process, their formation is ultimately permitted by local ischemic necrosis.
Abscesses present with localized pain, fever, and leukocytosis,and can be definitively diagnosed by ultrasound or CT .
The likelihood of abscess formation has been strongly linked to a history of a Whipple procedure:
the presence of a bilioenteric anastomosis increases the incidence of a hepatic abscess by an odds ratio of 894 .
Attempts at prophylaxis against the formation of abscesses have led many clinicians to treat patients with broadspectrum antibiotics peri- and postoperatively ; others have even advocated
the addition of antibiotics to the embolic mixture.
However, a recent prospective cohort study from Germany casts doubt on these practices: patients who did not receive treatment with antibiotics had no more infections or other complications than those who received 3 days of intravenous and 7 days of oral broad-spectrum antibiotics .
Severe ischemic complications, other than abscesses, have been reported to occur in 2.1% of patients receiving chemoembolization: these consist of ischemic cholecystitis (1.1%), bile duct necrosis (1.1%) , and perforation of the duo denum (0.05%) .
However, several other studies have quoted the incidence of gastroduodenal erosions and ulcerations to be significantly higher: one retrospective analysis of 280 cases demonstrated an endoscopy-proven incidence of 5.3% .
Since such lesions can result from the reflux of embolic material into the gastric circulation, the importance of meticulous attention to anatomic variants and adherence to selective or superselective embolization is the primary safeguard against this possibility .
Alternatively, at least some of these lesions could be the result of stress ulceration. Similarly, embolization distal to the cystic artery is the primary way of avoiding ischemic cholecystitis .
Nevertheless, since chemoembolization purposefully causes tissue ischemia, some damage to structures that are dependent on the hepatic artery is unavoidable (e.g., the intrahepatic bile
Renal failure has also been documented as a complication of chemoembolization, though its reported incidence varies between 0.05%  and 13%, averaging 1.8% in the aforementioned meta-analysis .
A prospective cohort study revealed an incidence of 8.6%, with 2.9% developing irreversible renal impairment .
Independent risk factors for the development of acute renal failure are the number of chemoembolization sessions, high Child–Pugh class, and a severe course of post-embolization syndrome; irreversible renal dysfunction was predicted only by the presence of diabetes .
The proximate causes of such kidney damage may be
the use of arterial contrast agents, the nephrotoxicity of the chemotherapeutic drugs, and inflammatory factors released from tumor necrosis [8,45].
The less common complications of chemoembolization include tumor rupture, occlusion of the hepatic artery, and clinically significant pancreatitis.
Spontaneous rupture of the treated tumor occurs in 0.15% of patients, most often after the
embolization of a large neoplasm .
Occlusion of the hepatic artery is a complication of repeated embolizations, occurring in 2% of patients following their second or third round of chemoembolization .
Though clinically significant pancreatitis is generally considered a rare complication – Roullet et al. report an incidence of 1.7%  – subclinical elevations in pancreatic enzymes may occur in as many as 15.2% of patients .
The likelihood of suffering severe side effects from chemoembolization is attenuated by both meticulous technique and proper patient selection. In principle, patients must be selected to include only those who will both benefit and tolerate the embolization procedure.
Selecting patients for optimum efficacy
Patients with multiple or unresectable lesions located exclusively or predominantly in the liver are ideal candidates for chemoembolization.
Since liver embolization only targets intrahepatic lesions, patients whose hepatic tumor burden is the primary driver of their symptoms and survival are the most likely to benefit from chemoembolization.
Nevertheless, the presence of some extrahepatic disease is not an absolute contraindication to chemoembolization; some patients whose metastatic disease is minimal or indolent may still be candidates for this therapy.
Selecting patients for optimum tolerability
The fundamental principle underlying the intra-arterial embolo-therapies is the differential blood supply of the hepatic neoplasms (supplied via the hepatic artery) and hepatocytes (supplied via the portal vein). Thus, if the native hepatocytes were to become more dependent on the blood flow from the hepatic artery,embolization of this vessel would be expected to lead to increased side effects.
This has in fact been demonstrated. Conditions that predispose the healthy liver to injury by increasing the relative contribution of blood from the arterial circulation include portal vein thrombi and superimposed liver disease.
Thus, occlusion of the portal vein is a relative contraindication to chemoembolization, though small
case series suggest that patients with the significant collateral flow can still be embolized
Patients with significant liver disease, such as those of Child-Pugh class C, with tumor replacing > 50% of liver , alpha-fetoprotein > 400 U L−1 , lactate dehydrogenase > 425 IU L−1, aspartate aminotransferase > 100 IU L−1, or total bilirubin ≥ 2 mg dL−1, are also at increased risk. Severe liver disease, as indicated by hepatic encephalopathy or jaundice, is an absolute contraindication to embolization.
Biliary pathology is another relative contraindication. Biliary obstruction predisposes patients to biliary necrosis even in the absence of hyperbilirubinemia.
As discussed previously, a surgical biliary anastomosis or stent virtually guarantees the development of a hepatic abscess, at least in the absence of prophylactic antibiotics .
Last, since the chemoembolization procedure must include angiography, patients with contraindications to this procedure cannot be embolized. All of the contraindications for chemoembolization also apply to bland embolization.
New developments in chemoembolization technology
The latest generation of embolic particles are polyvinyl alcohol polymeric beads specifically designed to load chemotherapeutic drugs and elute them over time into the tumor tissue following embolization.
Preclinical bench-top and animal studies have confirmed the ability of these drug-eluting beads to provide enhanced local drug delivery over a prolonged period with minimal systemic exposure
Phase I/II clinical trials for hepatoma in Europe and Asia have shown promising 1-year and 2-year survivals in the 85–90% range, but a disturbing incidence of major complications at around 10%, with a surprising frequency of hepatic abscess [52,53].
Randomized trials against conventional oily chemoembolization have not been completed. These beads are available as bland embolics in the USA and can be loaded with one or more drugs, but such off-label use is discouraged until their safety and efficacy is established in clinical trials, particularly given their high cost.
Transarterial chemoembolization is a powerful and well-established tool in the palliative management of both primary and secondary liver tumors.
While future randomized trials are still needed to unequivocally prove the survival benefits of
chemoembolization in some cancers, its effects on the management of symptoms have been clearly demonstrated.
When performed with meticulous technique, chemoembolization can be efficacious while still maintaining a side-effect profile superior to that of conventional therapies.
Though patient selection remains crucial, the transarterial embolotherapies can be offered to many more patients than traditional hepatic resection or transplantation.
Therefore, familiarity with chemoembolization is essential for any clinician involved in the care of patients with primary or secondary liver tumors.
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High-intensity focused ultrasound (HIFU)
treatment of liver cancer