Embolization Therapy: Principles and Clinical Applications, 1 Ed.

Oil-Based Chemoembolization

Marcus Presley • Daniel B. Brown

Hepatocellular carcinoma (HCC) remains a uniformly lethal disease process in the absence of curative procedures such as transplantation or resection. Okuda et al.1 described a median survival of 1.6 months for untreated patients in 1984. The dismal prognosis for patients with HCC is largely unchanged, with a median survival of 3 months reported in a prospectively evaluated group in 2005.2 For decades, no systemic therapies were available and resection remains largely infeasible given the nearly universal presence of cirrhosis. In 1975, a series of 14 patients treated with systemic doxorubicin for HCC with 3 responders was reported.3 A similar 16.6% response rate was identified in a 42-patient cohort in 1977.4 Intra-arterial doxorubicin was then studied, and when infusion was performed with embolization, survival was extended to 19 months.5,6 These reports spurred interest in further development of chemoembolization of HCC.

Several randomized trials were performed in the 1990s without evidence of benefit from chemoembolization. These studies had various flaws in their construction, including treatment of patients at timed intervals rather than based on imaging findings, poor patient selection, limited sample size unlikely to demonstrate statistical benefit, and inappropriate choice of embolic agents such as coils which limited the ability to retreat patients.710

In 2002, two prospective randomized trials were published demonstrating that in appropriately selected patient populations, chemoembolization resulted in superior survival compared to symptomatic treatment. Lo et al.11randomized 80 patients to either chemoembolization with cisplatin, Lipiodol, and gelfoam or best supportive care with survival as the primary end point. Patients were carefully selected with exclusion of individuals with advanced cirrhosis or macroscopic vascular invasion. Survival rates at 1, 2, and 3 years following chemoembolization were 57%, 31%, and 26%, respectively, compared to 32%, 11%, and 3% for supportive care (P = .002). Llovet et al.12performed a three-arm trial comparing chemoembolization, bland embolization, and best supportive care in a total of 112 patients with a primary end point of survival. The trial was halted when the chemoembolization group reached superiority versus supportive care with 1- and 2-year survivals of 82% and 63%, respectively, compared to 63% and 27% (P = .025). The outcomes from these two studies lent significant credibility to the practice of chemoembolization.

DEVICE/MATERIAL DESCRIPTION

Oily chemoembolization is one of the most cost-effective treatment options in all of interventional oncology. The cost of the chemotherapy, Lipiodol, and embolic is much less than drug-eluting beads or yttrium 90 (90Y) microspheres. A challenge when comparing outcomes from different studies is the tremendous variation in embolics, chemotherapeutic agents, and how these tools are combined in a given procedure. This issue is further clouded by the absence from the marketplace of some of the widely reported agents over the last decade. At various times, Ethiodol, powdered cisplatin, and powdered doxorubicin have been unavailable. As a result of the mentioned variables, standardization of chemoembolization has been difficult to achieve.

The embolic agent of choice varies by study. In the previously mentioned randomized trials of Lo et al.11 and Llovet et al.,12 gelfoam was the embolic agent. Other authors have used polyvinyl alcohol with a transition to use of calibrated embolic microspheres as they became available.1315 However, direct comparisons of outcomes in oily chemoembolization with different embolic agents are sparse. One review compared gelfoam powder with polyvinyl alcohol and Ethiodol and resulted in nearly identical survival: 519 ± 80 days for gelfoam powder versus 511 ± 75 days for polyvinyl alcohol (P = .93).16

Literature comparing different chemotherapy regimens is more plentiful. Of note, no prospective randomized trial has identified a statistically significant difference in targeted outcomes when comparing regimens1723 (Table 35.1). One prospective study compared epirubicin to doxorubicin without any difference in survival identified at 1, 2, or 3 years.24 Given the intermittent unavailability of powdered doxorubicin, this finding suggests that epirubicin could be an adequate alternative.

A final consideration is timing the addition of embolics to the chemotherapy/oil mixture. A comparison of various approaches was compared by Geschwind et al.25 They studied the percentage of intended chemotherapy that could be infused as well as the subsequent arterial patency in a treated area. Patients received one of three regimens: chemotherapy, oil, and polyvinyl alcohol particles simultaneously; chemotherapy and oil followed by polyvinyl alcohol; or chemotherapy and oil followed by gelfoam. When the embolic was mixed simultaneously with the chemotherapy and oil, both the intended percentage of chemotherapy to be infused as well as the subsequent arterial patency was lower than when embolics were added following oil/chemotherapy infusion. Outcomes for polyvinyl alcohol and gelfoam were similar regarding percentage of chemotherapy delivery (75.3% polyvinyl alcohol vs. 80.6% gelfoam) and subsequent arterial patency (74% polyvinyl alcohol vs. 81% gelfoam).

The delivery equipment is relatively standard for interventional radiology laboratories and includes arterial sheaths, selective catheters, and microcatheters. For patients with HCC, selection of segmental and subsegmental arteries is typically performed, making microcatheters a necessity for most, if not all, procedures. Microcatheters with 0.027-in lumens can perform diagnostic angiography as well, tolerating power injection rates up to 4 mL per second. The ability to perform high-quality angiography via the microcatheter is supplemented by the expanding use of C-arm computed tomography for targeting in this patient population. The viscosity of the chemotherapy and oil can make injection through smaller lumen catheters challenging, another reason to use larger bore devices. The mixture of oil and chemotherapy is toxic and can melt the junction of standard stopcocks and syringes with potential leakage of contents. At the advent of the procedure, glass syringes and metal stopcocks were used to avoid this issue. Currently, we use syringes and stopcocks made of polycarbonate. Although polycarbonate has made chemoembolic suspension less cumbersome, there is still potential for leakage and operators should operate with great care.

TECHNIQUE

Preprocedure Considerations

Patients should have either a dynamically enhanced computed tomography (CT) or magnetic resonance (MR) scan within 4 weeks of treatment. We hydrate patients with approximately 100 mL per hour of normal saline unless there is a history of congestive heart failure or other cardiac disease in which case lower rates are given. Patients are given midazolam and fentanyl for moderate sedation and ondansetron to control nausea. Labs are reviewed the morning of the procedure. When treating HCC, elevated bilirubin is a common scenario secondary to underlying cirrhosis. Historically, patients with total serum bilirubin greater than 2 mg/dL were approached with great caution. With a superselective approach, treatment of a small portion of the liver is possible, allowing for safe treatment in patients with liver dysfunction. Thrombocytopenia is also commonly present in cirrhotics as a consequence of portal hypertension. We do not routinely transfuse platelets as consumption by the engorged spleen will frequently limit the response. Preprocedure antibiotics are not required in patients with intact biliary anatomy (see complications section).

Procedural Considerations

Access to the femoral artery is obtained using the Seldinger technique, and a 6-Fr sheath is placed and connected to a pressurized flush. A 5-Fr selective catheter is used to select the superior mesenteric and celiac arteries and diagnostic arteriography performed. With advances in cross-sectional imaging, aberrant anatomy is frequently identified preprocedure that allows for targeted angiography with smaller volume contrast injections. Following selective angiography of the mesenteric artery, subselection with a microcatheter is performed over a hydrophilic microwire. Repeat digital subtraction angiography (DSA) is performed at the lobar or segmental level depending on the tumor location. If there is concern regarding complete tumor coverage in the selected area, we will perform C-arm CT with the reconstructed images compared to the preprocedure imaging. Once we confirm that the targeted area has been selected, the oil and chemotherapy mixture is suspended via a three-way stopcock. We use 1 mL of oil for each centimeter of tumor diameter up to 15 mL. Following injection of 4 to 6 mL of intra-arterial lidocaine, the suspended mixture is slowly infused using 3-mL syringes under fluoroscopic guidance, ensuring that antegrade flow is maintained. Once the entire mixture is infused, gelfoam slurry is added until the segmental artery reaches near stasis. If stasis is achieved before infusion of the entire slurry of chemotherapy, the gelfoam is added at that time. Final DSA is performed to evaluate for residual tumor enhancement. Our preference is to use closure devices in this patient group to decrease recumbency time due to postprocedural nausea and vomiting and the common incidence of thrombocytopenia. In our experience, success rates with closure devices are not adversely affected in the presence of thrombocytopenia.

Postprocedure Considerations

Patients are admitted overnight for hydration and pain control. Empiric ondansetron (8 mg) is given every 8 hours and a patient-controlled analgesia (PCA) pump is ordered, using Dilaudid 0.1 mg demand dose every 6 minutes without a basal rate. This level of analgesia is sufficient for over 90% of patients. Patients are started on a clear diet that is advanced as tolerated. Labs are rechecked overnight to ensure liver functions remain stable. The key components to discharge the next morning are the ability to tolerate oral intake and pain control with oral medications. During morning rounds, the PCA usage and patient pain scale is assessed. The PCA is discontinued if appropriate and the patient can be discharged following breakfast. We provide instructions on maintaining hydration following discharge and patients are asked to call interventional oncology if they are struggling with oral intake. Many times, early intervention with intravenous fluids in the clinic can avoid readmission. Patients are discharged with oral pain medication when appropriate as well as antiemetics. An appointment is made for follow-up imaging 4 weeks from treatment to assess treatment response.

CLINICAL APPLICATIONS

Chemoembolization is one of the most widely performed procedures for HCC because most patients present with cirrhosis too advanced to consider resection. Additionally, the number of patients requiring liver transplantation far outstrips the available supply of organs. To separate patients by disease status and prognosis, the Barcelona Clinic for Liver Cancer (BCLC) guidelines (Fig. 35.1) have been developed.26 In a review of over 1,700 patients, BCLC was a better predictor of survival than both alternative scoring systems and serum biomarkers.27 Survival was also relatively predictable by BCLC stage, with 5-year survival decreasing significantly with each advance in stage (Fig. 35.2).

Applying the criteria, patients without portal hypertension and with normal performance status and small solitary tumor (stage 0) may undergo resection safely, whereas transplantation is used for individuals with up to three tumors when all three are less than 3 cm (stage A). Patients with either larger tumors or a greater numerical burden are referred for chemoembolization (stage B). In the setting of a patient with a lesser performance status, portal venous invasion, and/or metastatic disease (stage C), targeted biologic therapy or a clinical trial may be offered. However, despite these recommendations, in clinical practice, chemoembolization remains widely performed with disease of lesser and greater severity than stage B (Fig. 35.2). Chemoembolization was used in 63% of stage 0, 54% of stage A, and 35.7% of stage C patients.27 For patients with a lesser burden of disease, treatments such as ablation may be infeasible due to challenging targeting, whereas in advanced disease, the cost of treatments such as sorafenib are considerable. Additionally, studies in patients with advanced disease have raised questions about the value added from biologic therapy.

The cost of biologic therapies is a significant consideration. Considering this factor, Kim et al.28 reviewed outcomes with sorafenib in advanced disease (BCLC stage C) and compared them to other treatments. There was no difference in overall survival between patients treated with sorafenib (8.4 months) and other therapies (8.2 months; P > .05). Sorafenib did provide better survival in patients with extrahepatic disease and infiltrative tumors. Similarly, Pinter et al.29 described similar time to progression with chemoembolization versus sorafenib (5.3 months vs. 3.8 months; P = .737). Overall survival was also not significantly different between treatments (9.2 months for chemoembolization vs. 7.4 months for sorafenib; P = .377). Patients with macroscopic portal vein invasion treated with sorafenib did not have improved survival compared to chemoembolization, despite this imaging finding serving as an indication for biologic therapy using the BCLC criteria.

Chemoembolization is frequently used to treat patients to facilitate transplantation. Patients who are within Milan criteria can receive treatment as a bridge to transplantation. Without therapy, the average drop-off rate for patients diagnosed with HCC within Milan criteria is 17% at 6 months and 32% at 1 year.30 For patients with prolonged wait times related to wait lists or documentation of sobriety, tumor treatment can potentially decrease the risk of progression and drop-off from the transplant list. Comparing chemoembolized patients to untreated matched controls, Frangakis et al.31 found an 80% decrease in the drop-off rate from the transplant list.

Chemoembolization has also been used to induce tumor necrosis in patients beyond the Milan criteria to allow listing for transplantation, an approach commonly referred to as downstaging. Chapman et al.32described successful downstaging in over one-third of stage III patients with eventual liver transplant. Only 1 of 17 transplanted patients developed recurrent disease after surgery, a solitary lung metastasis that was resected. This outcome is comparable to the 31% success rate with chemoembolization described by Lewandowski et al.33

Given the relative shortage of donor organs for liver transplantation, chemoembolization ultimately acts as definitive therapy for a great number of patients. Outside of clinical studies, patients treated with chemoembolization are frequently more ill. The study by Llovet et al.12 included just over 11% (112/908) of screened patients, and the study by Lo et al.11 enrolled only 21% of potential patients (80/387). Their trials excluded individuals with moderate liver dysfunction and any vascular invasion. Although these criteria are reasonable for a clinical trial, in day-to-day practice, many patients have significantly greater comorbidities. Several retrospective reviews (Table 35.2) provide insight into the expected survival of patients with HCC treated with oily chemoembolization.1315,34 These trials produced survivals ranging from 13 to 16 months but included “all comers” such as Child-Pugh B patients or those with vascular invasion. This outcome is not dissimilar to 90Y radioembolization. The largest nonrandomized trial evaluating 90Y included 291 patients.35 Survival for Child-Pugh A and B patients was 17.2 and 7.7 months, respectively, with a time to progression of 7.9 months for the entire group. Two retrospective trials comparing 90Y and chemoembolization have been performed.36,37 No significant difference in survival was found in either trial. Lance et al.37 reported 8-month survival with radioembolization versus 10.3 months with chemoembolization in a 73-patient cohort. In 245 treated patients, Salem et al.36 reported 20.5 months survival for radioembolization versus 17.4 months for chemoembolization. Both trials suggested less toxicity for the patients treated with radioembolization, a factor that may help determine the best route of therapy for patients with lesser performance status at presentation.

POTENTIAL COMPLICATIONS

Complications occur in approximately 10% of patients.38 Fortunately, most of these are minor. Death is reported following 2% to 3% of all chemoembolizations for all tumor types. The two most common complications in patients with HCC are liver failure, which occurs in 2.3% of patients, and readmission with prolonged postembolization syndrome, which is expected in 2% to 5% of patients.38 Less common complications include gastrointestinal ulceration, arterial dissection, pulmonary artery oil embolus, or surgical cholecystitis (all <1%). If the oily contrast mixture is inadvertently injected into the cystic artery, patients are more likely to present with prolonged postembolization syndrome.39 However, with pain control and hydration, most patients recover without requiring intervention. Most patients with HCC have not undergone biliary interventions such as stent placement or sphincterotomy that violates the sphincter of Oddi, resulting in colonized bile. In such patients, the risk of abscess formation following treatment is exponentially higher than in those without previous biliary interventions. In this setting, periprocedural antibiotics are universally prescribed and some operators include bowel preparation as well. Our approach is to use moxifloxacin, a fourth-generation fluoroquinolone which is excreted through the bile. Using this approach, Khan et al.40reported no abscesses following 25 infusions.

TIPS AND TRICKS

Scenario

Management

A patient with stable chronic borderline liver function has sudden elevation the day of procedure.

Labs in cirrhotic patients can be sensitive to minimal dehydration. If performance status and other labs are unchanged, we will often treat as scheduled and hydrate aggressively. If other labs have worsened or if performance has decreased, proceed with caution (if at all).

A patient with chronic stable borderline liver functions has sudden bilirubin elevation and worsening of other labs the day of the procedure.

This may still be related to hydration issues. Although the procedure for that day may need to be rescheduled, recheck labs in a week when the patient is not on nothing by mouth status.

My patient was treated with chemoembolization and has residual disease at the margin of the tumor. I cannot find the enhancement via DSA or C-arm CT via the hepatic artery.

Strongly consider that an extrahepatic collateral may be the source of the residual enhancement. Common arteries: locations of enhancement include the following:

• Inferior phrenic: dome

• Intercostal: posterior/lateral

• Internal mammary: anterior

The patient I treated yesterday has no pain but cannot eat at rounds.

Continue hydration throughout the morning and reassess at lunch. If tolerated, turn off the intravenous fluids and watch for 2 more hours, then discharge if OK.

A treated patient is calling from home with difficulty eating but is tolerating oral liquids.

Encourage continued hydration. This can include some sports drinks that have added electrolytes.

I was referred a patient with segmental portal vein thrombosis. Can chemoembolization be performed?

Segmental chemoembolization can be safely performed in the setting of normal liver functions.

A patient with tumor treated near the liver dome is calling with intractable pain.

Pain is often caused by capsular distension from postprocedural edema. Consider prescribing low-dose steroids for several days. Our preference is to use a methylprednisolone dose pack.

A patient with tumor treated near the liver dome is calling with intractable hiccups.

Consider prescribing haloperidol as an outpatient. Many patients are hesitant to take this medication, which can be used as a way to determine the severity of symptoms.

Following chemoembolization, a patient calls with excruciating right upper quadrant pain. CT in the emergency room demonstrates oily contrast in the gallbladder lumen.

Nontarget embolization of the gallbladder is typically managed with pain control and hydration. In most cases, nonoperative/noncatheter drainage management is adequate.

During chemoembolization, a branch of the left hepatic artery extends inferiorly and to the left, outside the apparent liver edge.

This finding likely represents a falciform artery. Treatment of this artery may result in skin erythema or necrosis. Options to prevent this include embolization of the branch or placement of an ice pack on the patient’s abdomen to induce vasospasm.

REFERENCES

 1. Okuda K, Obata H, Nakajima Y, et al. Prognosis of primary hepatocellular carcinoma. Hepatology. 1984;4(S1):3S–6S.

 2. Yeung YP, Lo CM, Liu CL, et al. Natural history of untreated nonsurgical hepatocellular carcinoma. Am J Gastroenterol. 2005;100(9):1995–2004.

 3. Olweny CL, Toya T, Katongole-Mbidde E, et al. Treatment of hepatocellular carcinoma with Adriamycin. Preliminary communication. Cancer. 1975;36(4):1250–1257.

 4. Ihde DC, Kane RC, Cohen MH, et al. Adriamycin therapy in American patients with hepatocellular carcinoma. Cancer Treat Rep. 1977;61(7):1385–1387.

 5. Wheeler PG, Nunnerley H, Melia WM, et al. The use of therapeutic embolisation at the time of hepatic arteriography in the management of primary tumours of the liver. Ann Acad Med Singapore. 1980;9(2):269–273.

 6. Bern MM, McDermott W, Cady B, et al. Intraaterial hepatic infusion and intravenous Adriamycin for treatment of hepatocellular carcinoma: a clinical and pharmacology report. Cancer. 1978;42(2):399–405.

 7. Bruix J, Llovet JM, Castells A, et al. Transarterial embolization versus symptomatic treatment in patients with advanced hepatocellular carcinoma: results of a randomized, controlled trial in a single institution. Hepatology. 1998;27(6):1578–1583.

 8. Madden MV, Krige JE, Bailey S, et al. Randomised trial of targeted chemotherapy with lipiodol and 5-epidoxorubicin compared with symptomatic treatment for hepatoma. Gut. 1993;34(11):1598–1600.

 9. Pelletier G, Roche A, Ink O, et al. A randomized trial of hepatic arterial chemoembolization in patients with unresectable hepatocellular carcinoma. J Hepatol. 1990;11(2):181–184.

10. Pelletier G, Ducreux M, Gay F, et al. Treatment of unresectable hepatocellular carcinoma with lipiodol chemoembolization: a multicenter randomized trial. Groupe CHC. J Hepatol. 1998;29(1):129–134.

11. Lo C-M, Ngan H, Tso W-K, et al. Randomized controlled trial of transarterial lipiodol chemoembolization for unresectable hepatocellular carcinoma. Hepatology. 2002;35(5):1164–1171.

12. Llovet JM, Real MI, Montaña X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734–1739.

13. Solomon B, Soulen MC, Baum RA, et al. Chemoembolization of hepatocellular carcinoma with cisplatin, doxorubicin, mitomycin-c, ethiodol, and polyvinyl alcohol: prospective evaluation of response and survival in a U.S. Population. J Vasc Interv Radiol. 1999;10(6):793–798.

14. Buijs M, Vossen JA, Frangakis C, et al. Nonresectable hepatocellular carcinoma: long-term toxicity in patients treated with transarterial chemoembolization—single-center experience. Radiology. 2008;249(1):346–354.

15. Gomes AS, Rosove MH, Rosen PJ, et al. Triple-drug transcatheter arterial chemoembolization in unresectable hepatocellular carcinoma: assessment of survival in 124 consecutive patients. AJR Am J Roentgenol. 2009;193(6):1665–1671.

16. Brown DB, Pilgram TK, Darcy MD, et al. Hepatic arterial chemoembolization for hepatocellular carcinoma: comparison of survival rates with different embolic agents. J Vasc Interv Radiol. 2005;16(12):1661–1666.

17. Yodono H, Matsuo K, Shinohara A. A retrospective comparative study of epirubicin-lipiodol emulsion and cisplatin-lipiodol suspension for use with transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma. Anticancer Drugs. 2011;22(3):277–282.

18. Lammer J, Malagari K, Vogl T, et al. Prospective randomized study of doxorubicin-eluting-bead embolization in the treatment of hepatocellular carcinoma: results of the PRECISION V study. Cardiovasc Intervent Radiol. 2010;33(1):41–52.

19. Sahara S, Kawai N, Sato M, et al. Prospective evaluation of transcatheter arterial chemoembolization (TACE) with multiple anti-cancer drugs (epirubicin, cisplatin, mitomycin c, 5-fluorouracil) compared with TACE with epirubicin for treatment of hepatocellular carcinoma. Cardiovasc Intervent Radiol. 2012;35(6):1363–1371.

20. Song MJ, Park CH, Kim JD, et al. Drug-eluting bead loaded with doxorubicin versus conventional lipiodol-based transarterial chemoembolization in the treatment of hepatocellular carcinoma: a case-control study of Asian patients. Eur J Gastroenterol Hepatol. 2011;23(6):521–527.

21. Dhanasekaran R, Kooby DA, Staley CA, et al. Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC). J Surg Oncol. 2010;101(6):476–480.

22. Kamada K, Nakanishi T, Kitamoto M, et al. Long-term prognosis of patients undergoing transcatheter arterial chemoembolization for unresectable hepatocellular carcinoma: comparison of cisplatin lipiodol suspension and doxorubicin hydrochloride emulsion. J Vasc Interv Radiol. 2001;12(7):847–854.

23. Petruzzi NJ, Frangos AJ, Fenkel JM, et al. Single-center comparison of three chemoembolization regimens for hepatocellular carcinoma. J Vasc Interv Radiol. 2013;24(2):266–273.

24. Kawai S, Tani M, Okamura J, et al. Prospective and randomized trial of lipiodol-transcatheter arterial chemoembolization for treatment of hepatocellular carcinoma: a comparison of epirubicin and doxorubicin (second cooperative study). The Cooperative Study Group for Liver Cancer Treatment of Japan. Semin Oncol. 1997;24(2)(suppl 6):38–45.

25. Geschwind JF, Ramsey DE, Cleffken B, et al. Transcatheter arterial chemoembolization of liver tumors: effects of embolization protocol on injectable volume of chemotherapy and subsequent arterial patency. Cardiovasc Intervent Radiol. 2003;26(2):111–117.

26. Llovet JM, Burroughs A, Bruix J. Hepatocellular carcinoma. Lancet. 2003;362(9399):1907–1917.

27. Kim BK, Kim SU, Park JY, et al. Applicability of BCLC stage for prognostic stratification in comparison with other staging systems: single centre experience from long-term clinical outcomes of 1717 treatment-naïve patients with hepatocellular carcinoma. Liver Int. 2012;32(7):1120–1127.

28. Kim HY, Park J-W, Nam B-H, et al. Survival of patients with advanced hepatocellular carcinoma: sorafenib versus other treatments. J Gastroenterol Hepatol. 2011;26(11):1612–1618.

29. Pinter M, Hucke F, Graziadei I, et al. Advanced-stage hepatocellular carcinoma: transarterial chemoembolization versus sorafenib. Radiology. 2012;263(2):590–599.

30. Freeman RB, Edwards EB, Harper AM. Waiting list removal rates among patients with chronic and malignant liver diseases. Am J Transplant. 2006;6(6):1416–1421.

31. Frangakis C, Geschwind J-F, Kim D, et al. Chemoembolization decreases drop-off risk of hepatocellular carcinoma patients on the liver transplant list. Cardiovasc Intervent Radiol. 2011;34(6):1254–1261.

32. Chapman WC, Majella Doyle MB, Stuart JE, et al. Outcomes of neoadjuvant transarterial chemoembolization to downstage hepatocellular carcinoma before liver transplantation. Ann Surg. 2008;248(4):617–625.

33. Lewandowski RJ, Kulik LM, Riaz A, et al. A comparative analysis of transarterial downstaging for hepatocellular carcinoma: chemoembolization versus radioembolization. Am J Transplant. 2009;9(8):1920–1928.

34. Brown DB, Chapman WC, Cook RD, et al. Chemoembolization of hepatocellular carcinoma: patient status at presentation and outcome over 15 years at a single center. AJR Am J Roentgenol. 2008;190(3):608–615.

35. Salem R, Lewandowski RJ, Mulcahy MF, et al. Radioembolization for hepatocellular carcinoma using yttrium-90 microspheres: a comprehensive report of long-term outcomes. Gastroenterology. 2010;138(1):52–64.

36. Salem R, Lewandowski RJ, Kulik L, et al. Radioembolization results in longer time-to-progression and reduced toxicity compared with chemoembolization in patients with hepatocellular carcinoma. Gastroenterology. 2011;140(2):497–507.e2.

37. Lance C, McLennan G, Obuchowski N, et al. Comparative analysis of the safety and efficacy of transcatheter arterial chemoembolization and yttrium-90 radioembolization in patients with unresectable hepatocellular carcinoma. J Vasc Interv Radiol. 2011;22(12):1697–1705.

38. Brown DB, Nikolic B, Covey AM, al. Quality improvement guidelines for transhepatic arterial chemoembolization, embolization, and chemotherapeutic infusion for hepatic malignancy. J Vasc Interv Radiol. 2012;23(3):287–294.

39. Leung DA, Goin JE, Sickles C, et al. Determinants of postembolization syndrome after hepatic chemoembolization. J Vasc Interv Radiol. 2001;12(3):321–326.

40. Khan W, Sullivan KL, McCann JW, et al. Moxifloxacin prophylaxis for chemoembolization or embolization in patients with previous biliary interventions: a pilot study. AJR Am J Roentgenol. 2011;197(2):W343–W345.

41. Iwazawa J, Ohue S, Hashimoto N, et al. Local tumor progression following lipiodol-based targeted chemoembolization of hepatocellular carcinoma: a retrospective comparison of miriplatin and epirubicin. Cancer Manag Res. 2012;4:113–119.