Locoregional therapy for HCC

HEPATOCELLULAR CARCINOMA (HCC):
MANAGEMENT
Pratap Sagar Tiwari
Part 1: Managing Advanced HCC (past, present & future perspectives)
Part 2: Radiotherapy in HCC (is there any role ?)
Part 3: Locoregional Therapies in HCC (guidelines & beyond)
Part 4: Surgery in HCC (limit and limitations ?)
Part 5: Liver transplantation (HCC Perspective)

PART 3
LOCOREGIONAL THERAPIES IN HCC
(GUIDELINES & BEYOND)
Clipart :http://www.scientificanimations.com/wiki-images/

HCC MX: OVERVIEW
Meets criteria for LT
?
Resectable ?
Locally
Advanced?
Advance HCC ? End stage HCC?
LT Surgery
Locoregional
Therapies
Chemotherapy BSC

LOCOREGIONAL THERAPY MODALITIES
Transarterial Chemoembolisation
(TACE)Per cutaneous Ethanol Injection (PEI)
Ablation therapies Vascular Intervention Therapies
Combination therapies/ Future DirectivesIrreversible Electroporation (IRE)
Microwave Ablation (MWA)
Radiofrequency ablation(RFA)
High-intensity focused ultrasound
(HIFU)
Hepatic artery infusion chemotherapy
(HAIC)
Transarterial Radioembolisation (TARE)
• Laser-induced thermotherapy
• Cryoablation
• Percutaneous acetic acid injection

Per cutaneous Ethanol Injection (PEI)
Ablation therapies

PERCUTANEOUS ETHANOL ABLATION/INJECTION(PEI)
 PEI for treatment of hepatic tumors was first described by Sugiura et al. [1] in 1983.
 PEI was recommended as the standard percutaneous treatment for early-stage, non-surgical
HCC in the 2001 guidelines of the EASL [2].
 PEI has been reported to induce chemical coagulative necrosis in 70-80% of HCC lesions ≤30
mm in diameter [3-5], 95% of tumours <2 cm[6–8], but 50% when of 3–5 cm diameter [6–8],
with survival of >50% at 5 years [9]. The best candidates are in Child-Pugh A stage with small
HCC [10].
 The ablation is limited to the lesion itself and may be suboptimal for the presence of internal
septa: residual nests of vital neoplasia inside or just close to the pseudocapsule are hence
detected in about one-third of cases during follow-up [11].
References are at the end of the slides.

PEI: THE PROCEDURE
 The procedure is discussed with the pt/patient’s family. Alternative treatments are discussed with
the pt so an informed choice can be made. The pt is instructed to fast for 8 hr before the
procedure, and a coagulation profile is checked. A combination of IV midazolam and fentanyl is
used for sedation and analgesia.
 The lesion or lesions are visualized via USG or CT . A single 20- or 22-gauge needle is inserted
into the deep portion of the lesion, or more than one needle is inserted if the lesion is >3 cm. It
is important to make as few passes as possible into the lesion because of possible reflux of
alcohol back through excessive needle tracks .
Lee MJ, et al. Percutaneous Ethanol Injection for the Treatment of Hepatic Tumors: Indications, Mechanism of Action, Technique, and Efficacy.AJR 1995;164:215-220

PEI: THE PROCEDURE
 Usually, most hepatologists inject approx 8-10 ml of alcohol per treatment session per lesion. However,
larger volumes of alcohol have been injected, depending on the pt’s tolerance.
 First, alcohol is injected in the deep part of the lesion, and then the needle is slowly withdrawn to the
more superficial part while alcohol continues to be injected. In this way, it is hoped that ethanol will be
distributed evenly through the lesion.
 After alcohol injection, the needle(s) are left in place for 2-3 min so reflux of alcohol along the track is
reduced. Reflux of alcohol along the needle track can lead to significant pain from penitoneal
irritation.
 Alternatively, gelatin sponge can be injected as the needle is withdrawn to prevent reflux of alcohol
Lee MJ, et al. Percutaneous Ethanol Injection for the Treatment of Hepatic Tumors: Indications, Mechanism of Action, Technique, and Efficacy.AJR 1995;164:215-220

PEI: THE PROCEDURE/RESPONSE
 The injection is repeated once or twice a week for up to six to eight sessions, depending on the
tumor size.
 The therapeutic effect of PEI can be evaluated by contrast CT scan.
 A CT scan was performed 1–3 days after the procedure to evaluate technique effectiveness (14).
Complete ablation was defined as hypoattenuation of the entire tumour without contrast
enhancement[1]. When the presence of unablated tumour portions was suspected, a few more
procedures were performed.
 Color Doppler USG and MRI are alternative imaging techniques for assessing the response to
PEI.[2,3](done every 4 months in a largest study[4]
1. Ebara M, Kita K, Sugiura N, et al. Therapeutic effect of percutaneous ethanol injection on small hepatocellular carcinoma: evaluation with CT. Radiology 1995;
195:371–377.
2. Lencioni R, Caramella D, Bartolozzi C. Hepatocellular carcinoma: use of color Doppler US to evaluate response to treatment with percutaneous ethanol injection.
Radiology 1995; 194:113–118.
3. Bartolozzi C, Lencioni R, Caramella D, et al. Treatment of hepatocellular carcinoma with percutaneous ethanol injection: evaluation with contrast-enhanced MR
imaging. AJR Am J Roentgenol 1994; 162:827–831.
4. Shiina S, et al. Percutaneous ethanol injection for hepatocellular carcinoma: 20-year outcome and prognostic factors. Liver Int. 2012 Oct; 32(9): 1434–1442.

PEI: INDICATIONS/CONTRAINDICATIONS
 It is generally agreed that pts with HCCs 3 cm or smaller and three or fewer in number are the
best candidates for PEI, although many centers perform PEI for HCCs up to 5 cm.[1-3]
 PEI is CI in the presence of gross ascites, severe thrombocytopenia, or coagulopathy (platelet
count <40,000/mm3, INR >1.75, in a study[5])because of a high risk of bleeding.
 Large infiltrative tumors, thrombosis in the main portal or hepatic vein, and extrahepatic
metastasis are also considered CIs in most centers.
 Pts with tumors on the surface of the liver are not favorable candidates for PEI because the
injected ethanol can leak back into the peritoneal cavity, and there is also a higher risk of tumor
implantation into the peritoneal cavity.[4]
1. Ebara M, Ohto M, Sugiura N, et al. Percutaneous ethanol injection for treatment of small hepatocellular carcinoma. Study of 95 patients. J Gastroenterol Hepatol 1990; 5:616–626.
2. Livraghi T, Bolondi L, Lazzaroni S, et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma in cirrhosis: A study on 207 patients. Cancer 1992; 69:925–929.
3. Di Stasi M, Buscarini L, Livraghi T, et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma. A multicenter survey of evaluation practices and complication rates. Scand J
Gastroenterol 1997; 32:1168–1173.
4. Shina S, Tagawa K, Unuma T, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma. A histopathologic study. Cancer 1991; 68:1524–1530.
5. brunello F, et al. Radiofrequency ablation versus ethanol injection for early hepatocellular carcinoma: A randomized controlled trial. Scandinavian Journal of Gastroenterology, 2008; 43: 727735

PEI: COMPLICATIONS
 The MC AES include fever, pain, and a feeling of alcohol intoxication. These are generally
transient and may only require symptomatic therapy.
 Depending on the site of the hepatic lesion, serious complications may occur.
 When a lesion is subdiaphragmatic, the pleura may be transgressed, with possible resulting
complications such as pneumothorax, pleural effusion, or hemothorax.
 Intrapenitoneal hemorrhage has been reported in three of 190 pts by Shiina et al. [1].
 Frequency of tumor seeding should theoretically be low because of the cytotoxic effect of
ethanol on any tumor cells that may find their way into the percutaneous track [2].
1. Shiina S, Niwa Y, Omata M. Percutaneous ethanol injection therapy for liver neoplasms. Semin Interient Radiol l993;1O(2):57-68
2. Zerbey AL, Mueller PA, Dawson SL, Hoover HC Jr. Pleural seeding from hepatocellular carcinoma: a complication of percutaneous alcohol ablation. Radiology l994

PEI: COMPLICATIONS
1. Shiina S, Niwa Y, Omata M. Percutaneous ethanol injection therapy for liver neoplasms. Semin Interient Radiol l993;1O(2):57-68
2. Zerbey AL, Mueller PA, Dawson SL, Hoover HC Jr. Pleural seeding from hepatocellular carcinoma: a complication of percutaneous alcohol ablation. Radiology l994
• PEI is a minimally invasive therapy with a good safety record.
• In a study of 746 pts with HCC treated by PEI, the treatment-related death rate was only 0.1%, and the rate
of severe complications was 1.7%.[1]
• A similar death rate (0.09%) and complication rate (3.2%) have been reported in a multicenter survey of
1,066 pts after PEI for HCC.[2]
• Tumor seeding along the needle track after PEI for HCC has been reported, with an incidence of 1% in a
study of 348 pts.[3]
1. Livraghi T, Giorgio A, Marin G, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection. Radiology 1995; 197:101–108.
2. Di Stasi M, Buscarini L, Livraghi T, et al. Percutaneous ethanol injection in the treatment of hepatocellular carcinoma. A multicenter survey of evaluation practices and complication rates. Scand J
Gastroenterol 1997; 32:1168–1173.
3. Ishii H, Okada S, Okusaka T, et al. Needle tract implantation of hepatocellular carcinoma after percutaneous ethanol injection. Cancer 1998; 82:1638–1642.

Ablation therapies
Outcome of PEI ?
PEI Vs LR ?
PEI Vs RFA ?
Outcome of RFA ?
RFA Vs LR ?
Radiofrequency Ablation (RFA)

RADIOFREQUENCY ABLATION (RFA)
 In the mid-1990s, RFA was proposed for the treatment of small
HCC [1,2].
 RFA is based on heat-generated coagulative necrosis that
induces the ablation of the tumour itself and may involve small
portions of surrounding liver tissue as well.
 In RFA, an electrical current is delivered through a needle
electrode under imaging or surgical guidance, producing heat-
based thermal cytotoxicity[3].
 Temperatures range between 60 °C to 100 °C and result in
almost instant coagulation necrosis[4].
1. Rossi S, Di Stasi M, Buscarini E, Quaretti P, Garbagnati F, Squassante L, et al. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. Am J Roengtenol 1996;167:75968.
2. De Baere T, Risse O, Kuoch V, Dromain C, Sengel C, Smayra T, et al. Adverse events during radiofrequency treatment of 582 hepatic tumors. Am J Roengtenol 2003;181:695700.
3. Goldberg SN, Gazelle GS, Mueller PR. Thermal ablation therapy for focal malignancy: a unified approach to underlying principles, techniques, and diagnostic imaging guidance. AJR Am J Roentgenol. 2000;174:323–331.
4. Gervais DA, Arellano RS. Percutaneous tumor ablation for hepatocellular carcinoma. AJR Am J Roentgenol. 2011;197:789–794.
Clipart from: https://www.alamy.com/radiofrequency-ablation-image66575282.html

RADIOFREQUENCY ABLATION (RFA)
• RFA is moderated by the heat-sink effect, a phenomenon that occurs when thermal energy is
dispersed from the target lesion due to blood flow in the vessels adjacent to it[1].
• Consequently, the shape and size of the ablation zone may be unpredictable and the efficacy of
RFA may be restricted as multiple sessions are necessary for complete tumour eradication[2].
• Caution is needed in treating lesions close to hollow viscera owing to the risk of perforation.
• Deep sedation is recommended.
1. Lu DS, Raman SS, Limanond P, Aziz D, Economou J, Busuttil R, Sayre J. Influence of large peritumoral vessels on outcome of radiofrequency ablation of liver
tumors. J Vasc Interv Radiol. 2003;14:1267–1274.
2. Mulier S, Ni Y, Jamart J, Ruers T, Marchal G, Michel L. Local recurrence after hepatic radiofrequency coagulation: multivariate meta-analysis and review of
contributing factors. Ann Surg. 2005;242:158–171.

RADIOFREQUENCY ABLATION (RFA): CI/COMPLICATIONS
 The ablation success rate for lesions <2 cm reaches 90% with a local recurrence rate of 1%[1].
For this reason, RFA is considered effective for tumours < 3 cm; combined LRT should be
considered for lesions > 3 cm[2].
 The main CI are severe bleeding diathesis (platelet count <50000/μL), ascites, jaundice and
presence of metallic devices such as pacemakers.
 RFA should also be avoided for tumours within 1 cm proximity to the hepatic portal tract.
 Major complications include liver failure, bleeding, infection, abscesses, intercostal nerve injury,
organ injury, tumour lysis syndrome and pneumothorax[3].
1. Livraghi T, Meloni F, Di Stasi M, Rolle E, Solbiati L, Tinelli C, Rossi S. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the treatment of choice?
Hepatology. 2008;47:82–89.
2. Peng ZW, Zhang YJ, Chen MS, Xu L, Liang HH, Lin XJ, Guo RP, Zhang YQ, Lau WY. Radiofrequency ablation with or without transcatheter arterial chemoembolization in the treatment of hepatocellular carcinoma: a prospective randomized trial.
J Clin Oncol. 2013;31:426–432.
3. Georgiades CS, Hong K, Geschwind JF. Radiofrequency ablation and chemoembolization for hepatocellular carcinoma. Cancer J. 2008;14:117–122.
4. Livraghi T, Solbiati L, Meloni MF, Gazelle GS, Halpern EF, Goldberg SN. Treatment of focal liver tumors with percutaneous radio-frequency ablation: complications encountered in a multicenter study. Radiology. 2003;226:441–451.
In a multicenter study of RFA for malignant liver tumours in 2320 pts, the rate of major complications reached
2.2% [4].

ASSESSING RESPONSE
 Typically the efficacy of percutaneous ablation therapy is assessed by dynamic cross-sectional
imaging (CT or MRI) one month after therapy.
 Standard methods to assess treatment response (eg, unidimensional Response Evaluation Criteria
in Solid Tumors [RECIST] criteria ) involve measurement of tumor dimensions before and after
treatment, but, methods such as these disregard the extent of necrosis, which is the end result of
locoregional ablative therapies [1].
 Others have proposed guidelines for assessment of response to locoregional ablative therapy
that are based upon reduction in viable tumor burden. Although not entirely reliable, the
absence of contrast uptake within the tumor is thought to reflect tumor necrosis, while the
persistence of contrast uptake indicates persistent disease. Recurrence of tumor in the treated
area (or elsewhere) is signaled by the reappearance of vascular enhancement.
1. Bruix J, Reig M, Rimola J, et al. Clinical decision making and research in hepatocellular carcinoma: pivotal role of imaging techniques. Hepatology 2011; 54:2238.

IMAGING RESPONSE CRITERIA USED IN EVALUATION OF
HCC AFTER TREATMENT
1. Modified from:
WHO handbook for reporting results of cancer treatment. World Health Organization, Geneva, 1979.
2. Yaghmai V, Besa C, Kim E, et al. Imaging assessment of hepatocellular carcinoma response to locoregional and systemic therapy. AJR Am J Roentgenol 2013; 201:80.
• A partially necrotic (black) HCC with an arterially-
enhancing (viable) component (white) is shown. The
arrows illustrate different measurements obtained for
assessment of response according to the various criteria.
 WHO measures two perpendicular dimensions of the entire
lesion;
 RECIST measures the single largest dimension of the
entire lesion;
 EASL measures perpendicular dimensions of just the
enhancing (viable) tumor;
 modified RECIST measures one single largest dimension of
the enchancing tumor.
• Both EASL criteria and modified RECIST are based upon
measurements obtained using cross sectional imaging (CT
or MRI) and contrast-enhanced arterial phase images.

MODIFIED RECIST FOR HEPATOCELLULAR CARCINOMA

OUTCOME?

PEI ; OUTCOME?
Shiina S, et al. Percutaneous ethanol injection for hepatocellular carcinoma: 20-year outcome and prognostic factors. Liver Int. 2012 Oct; 32(9): 1434–1442.
• Background: PEI is the best-known image-guided percutaneous ablation for HCC
and a well-tolerated, inexpensive procedure with few adverse effects. However,
there have been few reports on its long-term results.
• Aims: To report a 20-year consecutive case series at a tertiary referral centre.
• Methods: performed 2147 ethanol injection treatments on 685 primary HCC pts
and analysed a collected database.

BASELINE CHARACTERISTICS OF THE 685 PTS UNDERGOING PEI FOR PRIMARY
HCC
*Anti-HCV was not tested in 12 pts.
†Serum DCP level was not measured in 168 pts.
‡Serum AFP-L3 level was not measured in 461 pts.
HBs-Ag, hepatitis B surface antigen; HCV, hepatitis C
virus; AFP, α-fetoprotein; DCP, des-gamma-carboxy-
prothrombin; AFP-L3, lectin-reactive α-fetoprotein.
Data are expressed as mean ± standard deviation.

PEI ; OUTCOME?
• With a median follow-up of 51.6 months, 5-, 10-
and 20-year survival rates were 49.0% [95% CI=
45.3–53.0%], 17.9% (95% CI = 15.0–21.2%) and
7.2% (95% CI = 4..5–11.5%) respectively.

COMPLICATIONS IN 2147 TREATMENTS OF ETHANOL INJECTION FOR HCC

PEI ; OUTCOME?
Results
• Final CT demonstrated complete ablation of treated tumours in 2108 (98.2%) of 2147 RX.
• With a median follow-up of 51.6 months, 5-, 10- and 20-year survival rates were 49.0% [95% CI=
45.3–53.0%], 17.9% (95% CI = 15.0–21.2%) and 7.2% (95% CI = 4..5–11.5%) respectively.
• Multivariate analysis demonstrated that age, CP class, tumour size, tumour number and serum
AFP were significant prognostic factors for survival.
• Five-, 10- and 20-year local tumour progression rates were 18.2% (95% CI = 15.0–21.4%), 18.4%
(95% CI = 15.2–21.6%) and 18.4% (95% CI = 15.2–21.6%) respectively.
• There were 45 complications (2.1%) and two deaths (0.09%).
Conclusions:
• Ethanol injection was potentially curative for HCC, resulting in survival for more than 20 years.
• This study suggests that new ablation therapies will achieve similar or even better long-term results in HCC.

SURVIVAL RESULTS AFTER PEI THERAPY FOR HCC
Poon RTP, et al. Locoregional Therapies for Hepatocellular Carcinoma: A Critical Review From the Surgeon’s Perspective. ANNALS OF SURGERY Vol. 235, No. 4, 466–
486 References are included at the end of slides
Study/Year No. of
Patients
Tumor Size Survival %
1 year 3 year 5 year
Ebara et al,[1] 1990 95 <3 cm 93 65 28
Livraghi et al,[2] 1992 162 <5 cm 90 63 -
Castells et al,[3] 1993 30 ≤4 cm 83 55 -
Shiina et al,[4] 1993 146 1–6.5 cm 79 46 38
Isobe et al,[5] 1994 37 ≤2 cm 95 70 -
Lencioni et al,[6] 1995 105 <5 cm 96 68 32
Livraghi et al,[7] 1995 246
224
≤3 cm
3–5 cm
97
94
68
57
40
37
Orlando et al,[8] 1997 35 <4 cm 86 33 -
Castellano et al,[9] 1997 71 ≤5 cm 89 54 24
Lin et al,[10] 1999 47 ≤5 cm 85 61 -

 BACKGROUND: The objective of this study was to evaluate the indications for PEI performed in a
single session under general anesthesia for treating pts with LC and large (tumors > 5 cm) HCC,
and relevant survival curves.
 METHODS: Between November 1991 and November 1996, 108 pts were treated (a total of 128
procedures). They fell into 3 groups:
 GROUP A: 24 pts with single, encapsulated HCC measuring from 5-8.5 cm
 GROUP B: 63 pts with single, infiltrating HCC measuring from 5-10 cm or multiple HCC
 GROUP C: 21 pts with advanced disease, either hepatic (Child's Class C) or HCC with PVT.
 The mean amount of ethanol injected was 62 mL. The average hospital stay was 3.8 days. The
mean follow-up time was 40 months.
1. Livraghi T, Benedini V, Lazzaroni S, et al. Long-term results of single-session percutaneous ethanol injection in patients with large hepatocellular carcinoma.
Cancer 1998; 83:48–57.

RESULTS:
 The 1-, 2-, 3-, and 4-year survival rates were: 72%, 65%, 57%, and 44%, respectively, for Group A;
73%, 60%, 42%, and 18%, respectively, for Group B; and 46%, 25%, and 0%, respectively, for
Group C.
 Mortality was 0.7% (bleeding from esophageal varices in a Child's Class C patient).
 The rate of major complications was 4.6% (1 case of peritoneal hemorrhage, 1 case of severe liver
failure, 1 case of transient renal insufficiency, 1 case of peritoneal seeding, and 2 cases of
infarctions of a segment adjacent to the tumor).
1. Livraghi T, Benedini V, Lazzaroni S, et al. Long-term results of single-session percutaneous ethanol injection in patients with large hepatocellular carcinoma.
Cancer 1998; 83:48–57.

OUTCOME?
HAVE A DEFINITE ROLE IN EARLY STAGE OF HCC, GENERALLY ≤3CM
1 YR SURVIVAL: 90-95 %

PEI VS LIVER RESECTION ?
 OBJECTIVE: To compare disease recurrence and survival.
 METHODS: A total of 76 pts were randomly assigned to 2 groups based on treatment; all had
one or 2 tumors with diameter </=3 cm, with hepatitis without cirrhosis or Child class A or B
cirrhosis without evident ascites or bleeding tendency.
1. Huang GT, Lee PH, Tsang YM, Lai MY, Yang PM, Hu RH, Chen PJ, Kao JH, Sheu JC, Lee CZ, et al. Percutaneous ethanol injection versus surgical resection for the
treatment of small hepatocellular carcinoma: a prospective study. Ann Surg. 2005;242:36–42.

 RESULTS: Follow-up ranged from 12 to 59 months.
 Among PEI pts, 18 had recurrence 1 to 37 months . Three injection therapy patients died of 25, 37,
and 57 months after treatment.
 For the LR group, 15 had recurrence 2 to 54 months after treatment. Five resection patients died
of cancer at 11, 20, 23, 26, and 52 months, respectively.
 By Cox regression model and Kaplan-Meier survival analysis, there is no statistical significance for
recurrence and survival between treatment groups.
 However, tumor size larger than 2 cm and alpha-fetoprotein over 200 ng/mL correlated with
higher recurrence rate, and Child class B liver cirrhosis correlated with shorter survival.
1. Huang GT, Lee PH, Tsang YM, Lai MY, Yang PM, Hu RH, Chen PJ, Kao JH, Sheu JC, Lee CZ, et al. Percutaneous ethanol injection versus surgical resection for the
treatment of small hepatocellular carcinoma: a prospective study. Ann Surg. 2005;242:36–42.
CONCLUSIONS:
Percutaneous ethanol injection therapy appears to be as safe and effective as resection, and both treatments
can be considered first-line options for small hepatocellular carcinoma.

 On the other hand, Cho et al[1] reported that LR(n=113) had a trend towards better survival
profile as compared to PEI (n=1160) in HCC patients (5-year overall survival 65% vs 49%) (P =
0.059).
1. Cho YB, Lee KU, Suh KS, Kim YJ, Yoon JH, Lee HS, Hahn S, Park BJ. Hepatic resection compared to percutaneous ethanol injection for small hepatocellular
carcinoma using propensity score matching. J Gastroenterol Hepatol. 2007;22:1643–1649.

PEI IN LIVER METASTASES ?
 The effectiveness of PEI for the treatment of CLM is unclear. It was reported that
in more than 50% of cases of liver metastases < 4 cm, complete necrosis can be
obtained by means of PEI[1].
 Giorgio et al[2] (n=33) pts with 62 large (> 3.5 cm) reported that the survival
rates of pts with liver metastases who underwent PEI were 94%, 80%, 80%, and
44% at 12 mo, 24 mo, 36 mo, and 44 mo, respectively.
1. Giovannini M. Percutaneous alcohol ablation for liver metastasis. Semin Oncol. 2002;29:192–195
2. Giorgio A, Tarantino L, Mariniello N, De Stefano G, Perrotta A, Aloisio V, Del Viscovo L, Alaia A. [Ultrasonography-guided percutaneous ethanol injection in large an/or multiple liver metastasis]
Radiol Med. 1998;96:238–242

PEI; RECURRENCE RATE?
 One major concern of PEI for HCC is the high incidence of recurrence.
 The cumulative intrahepatic recurrence rates at 1, 3, and 5 years after PEI for small HCCs (5 cm)
were in the range of 26-32%, 51-81%, and 60- 83%, respectively, in reported series.[1-6]
 The majority of recurrences are new lesions at different portions of the liver, but local recurrence
at the site of the initial lesion treated by PEI accounted for 16-38% .[1,4,6]
 The substantial local recurrence rate may be a result of inhomogeneous diffusion of ethanol in
the tumor.
1. Shiina S, Tagawa K, Niwa Y, et al. Percutaneous ethanol injection therapy for hepatocellular carcinoma: results in 146 patients. AJR Am J Roentgenol 1993; 160:1023–1028.
2. Castellano L, Calandra M, Del Vecchio Blanco C, de Sio I. Predictive factors of survival and intrahepatic recurrence of hepatocellular carcinoma in cirrhosis after percutaneous ethanol injection: analysis of 71 patients. J Hepatol 1997; 27:862–
870.
3. Pompili M, Rapaccini GL, de Luca F, et al. Risk factors for intrahepatic recurrence of hepatocellular carcinoma in cirrhotic patients treated by percutaneous ethanol injection. Cancer 1997; 79:1501–1508.
4. Hasegawa S, Yamasaki N, Hiwaki T, et al. Factors that predict intrahepatic recurrence of hepatocellular carcinoma in 81 patients initially treated by percutaneous ethanol injection. Cancer 1999;861682–1690.
5. Khan KN, Yatsuhashi H, Yamasaki K, et al. Prospective analysis of risk factors for early intrahepatic recurrence of hepatocellular carcinoma following ethanol injection. J Hepatol 2000; 32:269–278.
6. Koda M, Murawaki Y, Mitsuda A, et al. Predictive factors for intrahepatic recurrence after percutaneous ethanol injection therapy for small hepatocellular carcinoma. Cancer 2000; 88:529–537.

PEI; RECURRENCE RATE?
 A high intrahepatic recurrence rate is also a major problem after LR of HCC.[1]
• Few studies have compared the recurrence rate after PEI and LR for small HCCs.
• In a retrospective study, Okuda[2] found similar rates of new lesions after PEI and LR in two
comparable groups of pts.
• However, In a study comparing two cohorts of pts with solitary HCCs ≤ 4 cm treated by PEI and
LR, the 2-year recurrence rates after PEI and LR were 66% and 45%, respectively, and the
difference was most obvious among pts with tumors 3 to 4 cm in size.[3]
• One advantage of PEI is its easy repeatability, which allows further treatment of both local and
distant intrahepatic recurrences.
• Thus, PEI can be used for treating recurrence in the liver remnant after resection of HCC.[1]
1. Poon RTP, Fan ST, Wong J. Risk factors, prevention and management of postoperative recurrence after resection of hepatocellular carcinoma. Ann Surg 2000; 232:10–24.
2. Okuda K. Intratumor ethanol injection. J Surg Oncol 1993(suppl); 3:97–99.
3. Castells A, Bruix J, Bru C, et al. Treatment of small hepatocellular carcinoma in cirrhotic patients: a cohort study comparing surgical resection and percutaneous ethanol injection. Hepatology
1993; 18:1121–1126.

• NOT ADEQUATE EVIDENCES TO DRAW A CONCLUSION
• HIGH INTRAHEPATIC RECURRENCE RATES WITH PEI
• PEI IN LIVER METS: INCONCLUSIVE
• NOT BENEFICIAL IN LARGER LESIONS (>3 CM) UNLIKE
SURGERY
• ADVANTAGES: EASY, CHEAP AND REPEATABILITY & CAN BE
USED FOR TREATING RECURRENCE IN THE LIVER REMNANT
AFTER RESECTION OF HCC.

RADIOFREQUENCY ABLATION: OUTCOME?
 Reported 3- and 5-year survival rates following RFA for pts fulfilling the Milan transplantation
criteria (single tumor <5 cm, or three or fewer tumors, each ≤3 cm) range from 70-91, and 48-77
%, respectively [1-3].
 Long-term outcomes are better in pts with smaller lesions [4-6]. In one series of 302 pts, the 3-
year survival rates for lesions >5 cm, 2.1 to 5 cm, and ≤2 cm were 59, 74, and 91 %, respectively
[4].
1. Lencioni R, Cioni D, Crocetti L, et al. Early-stage hepatocellular carcinoma in patients with cirrhosis: long-term results of percutaneous image-guided radiofrequency ablation. Radiology 2005;
234:961.
2. Takahashi S, Kudo M, Chung H, et al. Initial treatment response is essential to improve survival in patients with hepatocellular carcinoma who underwent curative radiofrequency ablation
therapy. Oncology 2007; 72 Suppl 1:98.
3. Choi D, Lim HK, Rhim H, et al. Percutaneous radiofrequency ablation for early-stage hepatocellular carcinoma as a first-line treatment: long-term results and prognostic factors in a large single-
institution series. Eur Radiol 2007; 17:684.
4. Tateishi R, Shiina S, Teratani T, et al. Percutaneous radiofrequency ablation for hepatocellular carcinoma. An analysis of 1000 cases. Cancer 2005; 103:1201.
5. Sala M, Llovet JM, Vilana R, et al. Initial response to percutaneous ablation predicts survival in patients with hepatocellular carcinoma. Hepatology 2004; 40:1352.
6. Livraghi T, Meloni F, Di Stasi M, et al. Sustained complete response and complications rates after radiofrequency ablation of very early hepatocellular carcinoma in cirrhosis: Is resection still the
treatment of choice? Hepatology 2008; 47:82.

RADIOFREQUENCY ABLATION: OUTCOME?
 In an analysis of five and 10-year survival following RFA in a Japanese series of
1170 pts with HCC, the majority of whom fulfilled the Milan criteria [1]. Five and
10-year survival rates were 60 and 27 %, respectively. While the five and 10-year
local progression rates were only 3 % each, the distant recurrence rates were 75
and 81 %, respectively.
 Local recurrence rates are variable, ranging from 2 to 36 percent in other studies
[2-6].
1. Shiina S, Tateishi R, Arano T, et al. Radiofrequency ablation for hepatocellular carcinoma: 10-year outcome and prognostic factors. Am J Gastroenterol 2012; 107:569.
2. Curley SA, Izzo F, Ellis LM, et al. Radiofrequency ablation of hepatocellular cancer in 110 patients with cirrhosis. Ann Surg 2000; 232:381.
3. Lencioni RA, Allgaier HP, Cioni D, et al. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection.
Radiology 2003; 228:235.
4. Horiike N, Iuchi H, Ninomiya T, et al. Influencing factors for recurrence of hepatocellular carcinoma treated with radiofrequency ablation. Oncol Rep 2002; 9:1059.
5. Hori T, Nagata K, Hasuike S, et al. Risk factors for the local recurrence of hepatocellular carcinoma after a single session of percutaneous radiofrequency ablation. J Gastroenterol 2003; 38:977.
6. Harrison LE, Koneru B, Baramipour P, et al. Locoregional recurrences are frequent after radiofrequency ablation for hepatocellular carcinoma. J Am Coll Surg 2003; 197:759.

FOLLOW-UP RESULTS AFTER RFA THERAPY FOR HCC
Study No. Tumor
Size (cm)
Route Mean FU
(mnths)
CN
%
RR
%
Survival
Rossi et al,[1] 1996 39 ≤3 P 22.6 95 41 1-yr, 94%, 3-yr,
68%
5-yr, 40%
Rossi et al,[2] 1998 23 ≤3.5 P 10 100 28 -
Allgaier et al,[3] 1999 12 - P 5 100 0 -
Francica & Marone,[4] 1999 15 1–4.3 P 15* 90 33 -
Curley et al,[5] 1999 48 - P (26), I (22) 15* 100 2.1 -
Nicoli et al,[6] 2000 47 1–6 P (33), I (14) 11.8 100 - 2-yr, 83%
Curley et al,[7] 2000 110 Mean 3.4 P (76), L (31), I (3) 19* 95 49 -
Poggi et al,[8] 2001 15 1.5–6.2 P 9.2 88 20 -
Buscarini et al,[9] 2001 88 ≤3.5 P 34 93 39 1-year, 89%
3-year, 62%
5-year, 33%

RFA VS LIVER RESECTION
 Two systematic reviews[1,2] showed no significant differences in OS between RFA and LR for HCC
within the Milan criteria, although RFA was a/with higher recurrence rates. (note: in study by Cho
YK (inc 2 RCT/550/550)stated as: OS for very early stage HCC, defined as an asymptomatic
solitary small HCC ≤ 2 cm, showed that primary RFA with a 9% local recurrence rate is
comparable to LR with a 3% operative mortality rate.)
 Zhou et al[3] performed a meta-analysis of 1 RCT and 9 controlled studies comparing
RFA(n=774) and LR(n=667) for HCC. The 5-year OS rate was borderline significant [OR 0.60
(0.36-1.01)]. RFA was a/with higher local recurrence [OR 4.50 (2.45-8.27)] and the disease-free
survival rates were significantly better for LR pts.
1. Cho YK, Rhim H, Noh S. Radiofrequency ablation versus surgical resection as primary treatment of hepatocellular carcinoma meeting the Milan criteria: a
systematic review. J Gastroenterol Hepatol. 2011;26:1354–1360.
2. Zhou Y, Zhao Y, Li B, Xu D, Yin Z, Xie F, Yang J. Meta-analysis of radiofrequency ablation versus hepatic resection for small hepatocellular carcinoma. BMC
Gastroenterol. 2010;10:78.
RFA VS LR
 OS: NO SIGNIFICANT DIFFERENCE
 RECURRENCE RATE: HIGHER IN RFA
 DISEASE FREE SURVIVAL: HIGHER IN LR

SUMMARY OF META-ANALYSES OF RFA VS LR IN HCC
Author RX N 5 YR Local
Recurrence (OR)
95% CI
5 YR Overall survival (OR)
95% CI
Changyong et al [1]
(inc 3 RCT)
LR
RFA
2313
2419
0.57 (0.50–0.65) P < 0.00001
Xu G et al [2]
(Inc 2 RCT)
LR
RFA
1233
1302 1.68 (1.21 to 2.34)
0.60 (0.43 to 0.84)
1. Chamhgyong E, et al. Efficacy comparison of radiofrequency ablation and hepatic resection for hepatocellular carcinoma: A meta-analysis. JCRT 2017;13 (4): 625-30
2. Xu gang, et al. Meta-analysis of surgical resection and radiofrequency ablation for early hepatocellular carcinoma. World Journal of Surgical Oncology 2012;10:163
XU G et al: The complication of LR was higher than RFA (OR, 6.25 (95%CI, 3.12 to 12.52); P = 0.000).

COMPARISON OF LR AND RFA FOR SMALL HCC: A META-
ANALYSIS OF 16,103 PTS
OS No of
studies
pts RFA (%) LR (%) OR [95% CI] P value
≤5 cm
3 YR 31 16,103 78.6 83.9 0.65 [0.53, 0.80] <0.001
5 YR 30 14,655 60.8 71.4 0.57 [0.48, 0.67] <0.001
≤3 cm
3 YR 19 13,298 81.2 85.7 0.62 [0.43, 0.89] 0.009
5 YR 16 13,075 61.8 71.9 0.55 [0.42, 0.72] <0.001
≤2 cm
3 YR 4 442 80.6 83.7 0.54 [0.12, 2.37] 0.41
5 YR 4 442 69.0 74.2 0.65 [0.27, 1.55] 0.33
Xu Q, et al. Comparison of Hepatic Resection and Radiofrequency Ablation for Small Hepatocellular Carcinoma: A Meta-Analysis of 16,103 Patients. Nature 2014

COMPARISON OF LR AND RFA FOR SMALL HCC: A META-
ANALYSIS OF 16,103 PTS
• The analysis showed that although LR was a/ with higher complication rate and
longer hospital-stay, LR is proposed as the first-line treatment rather than RFA
for pts with HCCs larger than 2 cm.
• For pts with HCCs of 2 cm or less, RFA may be an alternative to LR because of
their comparable long-term efficacy.
Xu Q, et al. Comparison of Hepatic Resection and Radiofrequency Ablation for Small Hepatocellular Carcinoma: A Meta-Analysis of 16,103 Patients. Nature 2014

RFA VS LIVER RESECTION IN CLM
 Wu et al[1](non RCT) metanalysis that compared RFA and LR for solitary CLM showed that LR
was better than RFA in terms of 5-year overall survival, as well as local control of the disease.
 Amerongen et al [2] also showed similar results.
1. Wu YZ, Li B, Wang T, Wang SJ, Zhou YM. Radiofrequency ablation vs hepatic resection for solitary colorectal liver metastasis: a meta-analysis. World J Gastroenterol.
2011;17:4143–4148.
2. Amerongen MJ,et al. Radiofrequency ablation compared to surgical resection for curative treatment of patients with colorectal liver metastases – a meta-analysis.
HPBONLINE September 2017Volume 19, Issue 9, Pages 749–756
Author DX RX N Local Recurrence (OR) Overall survival (OR)
Wu et al[1] CLM LR
RFA
273
574
-
4.89, 95% CI: 1.73-
13.87, P = 0.003
0.41, 95% CI: 0.22-
0.90, P = 0.008(5 yr)
-
Amerongen et al
[2]
CLM RFA
LR
1060
1817
1.66, 95%
CI = 1.15–2.40, P = 0.007
2.35, 95% CI = 1.49–3.69,
P = 0.001(5 yr)

RFA VS LIVER RESECTION IN CLM
• In conclusion, RFA is a minimally invasive modality for the treatment of CLM which has lower complication
rates as compared to LR.
• However, RFA is also currently a/with increased recurrence rates and lower disease-free and overall survival
and should therefore only be used for pts who are not optimal candidates for surgery.
• Furthur RCT is needed for definite summary.

RFA LR
Less Invasive Invasive
Less Complications More Complications
Short hospital stay Longer hospital stay
Cost effective Cost ineffective
Above benefit more on tumor <3 cm (limited ablation
volume)
Unrelated to size, provided adequate FHR
High recurrence (Heat sink effect/needle tract
seedling)
Less recurrence
Not suitable for specially located tumors, such as
underneath the liver capsule, the adjacent Gb, or
diaphragm. (Technically infeasible tumors)
Allows the identification of histological parameters
that predict recurrence risk.
Similar efficacy to LR in CP-A , HCC<3 CM
If LT is not feasible, ablation could be considered as the first-line option for pts with very early-stage HCC, and LR
could be second line for pts in whom ablation cannot be done or fails.[1]
1. Forner A,et al. Hepatocellular carcinoma. Lancet 2018; 391: 1301–14

PEI VS RFA ?
Lencioni RA. Small hepatocellular carcinoma in cirrhosis: randomized comparison of radio-frequency thermal ablation versus percutaneous ethanol injection.
Radiology. 2003 Jul;228(1):235-40. Epub 2003 May 20.
PURPOSE: To compare the effectiveness of RFA with that of PEI for the RX of small HCC in pts with cirrhosis.
MATERIALS AND METHODS: A series of 102 pts with LC and either single HCC 5 cm in diameter or smaller or
as many as three HCCs each 3 cm or smaller (overall number of lesions, 142) randomly received either RFA (n
= 52) or PEI (n = 50) as the sole first-line anticancer treatment.
Mean follow-up was 22.9 months +/- 9.4 (SD) in the RF group and 22.4 months +/- 8.6 in the PEI group.

PEI VS RFA ?

PEI VS RFA ?
• One- and 2-year local recurrence-free survival rates were 98%
and 96% in the RF group and 83% and 62% in the PEI group,
respectively (RR = 0.17; 95% CI: 0.06, 0.51; P =.002).

PEI VS RFA ?
• RESULTS: One- and 2-year survival rates were 100% and 98% in the RF group and 96% and 88% in the
PEI group, respectively ( RR = 0.20; 95% CI: 0.02, 1.69; P =.138).
• One- and 2-year local recurrence-free survival rates were 98% and 96% in the RF group and 83% and
62% in the PEI group, respectively (RR = 0.17; 95% CI: 0.06, 0.51; P =.002).
• One- and 2-year event-free survival rates were 86% and 64% for the RF group and 77% and 43% for the PEI
group, respectively (RR = 0.48; 95% CI: 0.27, 0.85; P =.012).
CONCLUSION: RFA is superior to PEI with respect to local recurrence-free survival
rates.

 To compare PEI, the standard approach which has been used for many years to treat early non-
surgical HCC in cirrhotic pts, and RFA, which has become an interesting alternative.
 MATERIAL AND METHODS: A randomized trial was carried out on 139 cirrhotic pts in C-P A/B
with 1-3 nodes of HCC (diameter 15-30 mm), for a total of 177 lesions.
 Pts were randomized to receive RFA (n=70) or PEI (n=69).
 The pEP was complete response (CR) 1 year after the percutaneous ablation of all HCC nodes
identified at baseline.
 sEP : early (30-50 days) CR, complications, survival and costs.

The OS rate was not significantly different in
the RFA versus PEI arm (HR=0.88, 95% CI:
0.50-1.53).

 Twenty-three pts in the PEI arm needed a second cycle of treatment, whereas just 9 of the RFA
arm underwent a second cycle.
 Treatment failures were 20 (2 patients died) in the PEI arm and 3 in the RFA arm.
 Complications occurred in 10 (14.3%) of the 70 pts treated by RFA and in 12 (17.4%) of the 69
treated by PEI (p0.616).
 There were 4 major complications: 2 in the RFA arm (1 haemoperitoneum; 1 right haemothorax
that needed urgent thoracotomy) and 2 in the PEI arm (1 haemoperitoneum ; 1 death).
 The fatality occurred in a man, aged 78 years, who was treated by PEI for two lesions and
developed thrombosis of the left portal branch; the patient died 10 days after the procedure with
a clinical syndrome suggestive of bowel infarction, and the necropsy showed diffuse ischaemic
damage to the small bowel. The fatality was considered possibly to be related to PEI.
 No case of seeding was observed.

 RESULTS: In an intention-to-treat analysis, 1-year CR was achieved in 46/70 (65.7%) and in 25/69
(36.2%) patients treated by RFA and PEI, respectively (p=0.0005).
 For lesions >20 mm in diameter, there was a larger CR rate in the RFA group (68.1% versus
26.3%).
 An early CR was obtained in 67/70 (95.7%) pts treated by RFA compared with 42/64 (65.6%) pts
treated by PEI (p=0.0001).
 Complications occurred in 10 and 12 pts treated by RFA and PEI, respectively.
 The OS rate was not significantly different in the RFA versus PEI arm (adjusted HR=0.88, 95% CI:
0.50-1.53).
 There was an incremental health-care cost of 8286 euro for each additional pt successfully
treated by RFA.
CONCLUSIONS: The 1-year CR rate after percutaneous treatment of early HCC was significantly better with
RFA than with PEI but did not provide a clear survival advantage in cirrhotic pts.

SUMMARY OF META-ANALYSES OF RFA VS PEI
Author DX RX N Local Recurrence (RR) Overall survival (RR)
Bouza et al[1] HCC RFA
PEI
396
391
0.37 (0.23-0.59) 1.24 (1.05-1.48) (4 yr)
1. Bouza C, López-Cuadrado T, Alcázar R, Saz-Parkinson Z,Amate JM. Meta-analysis of percutaneous radiofrequency ablation versus ethanol injection in
hepatocellular carcinoma. BMC Gastroenterol 2009; 9: 31
• Six studies were eligible. (5 RCT ,1 qRCT ). In general, subjects were in CP-A (74%) and had unresectable
HCC (mean size 2.5 cm). Mean follow-up was 25 +/- 11 months.
• The survival rate showed a significant benefit for RFA over PEI at one, two, three and four years. The
advantage in survival increased with time with Relative Risk values of: 1.28 (95%CI:1.12-1.45) and 1.24
(95%CI:1.05-1.48) for RFA versus PEI at 3- and 4-years respectively.
• Likewise, RFA achieved significantly lower rates of local recurrence (RR: 0.37, 95%CI: 0.23-0.59).
• The overall rate of AEs was higher with RFA (RR:2.55, 95%CI: 1.8-3.6) yet no significant differences were
found .

PERCUTANEOUS ACETIC ACID INJECTION
 The efficacy of PEI is limited by the presence of septa in the tumor nodule, which prevents
uniform diffusion of ethanol and necessitates repeated treatment sessions. Further, capsular
invasion cannot be ablated because ethanol cannot dissolve the fibrous capsule. Percutaneous
acetic acid injection (PAI) has been used as an alternative.[1]
 Acetic acid has a stronger necrotizing power than ethanol because it can dissolve lipids and
extract collagen. Its low pH induces swelling of the fibers and promotes dissociation of
intermolecular collagen cross-links.
1. Ohnishi K, Ohyama N, Ito S, Fujiwara K. Small hepatocellular carcinoma: treatment with US-guided intratumoral injection of acetic acid. Radiology 1994; 193:747–
752.

PERCUTANEOUS ACETIC ACID INJECTION
 One randomized controlled trial conducted in 60 pts with HCCs smaller than 3 cm showed that
the survival of pts treated with PAI was significantly better than those treated with PEI (2-year
survival rate, 92% vs. 63%).[1]
 The local recurrence rate was also significantly lower in the PAI group compared with the PEI
group (2-year local recurrence rate, 10% vs.44%).
 In that study, major treatment-related complications were rare with both modalities. However, no
further data are available to confirm the advantages of PAI over PEI.
1. Ohnishi K, Yoshioka H, Ito S, Fujiwara K. Prospective randomized controlled trial comparing percutaneous acetic acid injection and percutaneous ethanol injection
for small hepatocellular carcinoma. Hepatology 1998; 27:67–72.

PEI VS PAI VS RFA ?
 BACKGROUND & AIMS: To evaluate the evidence comparing RFA, PEI and PAI using meta-
analytical techniques.
 METHODS: Literature search was undertaken until December 2008 to identify comparative studies
evaluating survival, recurrence, complete necrosis of tumour and complications. Only randomized
clinical trials and quasi-randomized studies were included.
1. Germani G, Pleguezuelo M, Gurusamy K, Meyer T, Isgrò G, Burroughs AK. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid
injection for hepatocelullar carcinoma: a meta-analysis. J Hepatol. 2010 Mar;52(3):380-8. doi: 10.1016/j.jhep.2009.12.004. Epub 2010 Jan 17.

PEI VS PAI VS RFA ?
 RESULTS: Eight studies were identified: RFA vs. PEI (n=5), PAI vs. PEI (n=2) and RFA vs. PAI vs. PEI (n=1) including
1035 pts.
 PAI did not differ significantly from PEI for survival (OR 0.55; 95% CI 0.23-1.33; p=0.18), and local recurrence but
required less sessions.
 PAI had similar outcomes, except local recurrence, to RFA in the direct and indirect comparison.
 RFA was superior to PEI for survival (OR 0.52; 95% CI 0.35-0.78; p=0.001), complete necrosis of tumour and local
recurrence.
 For tumours ≤2 cm RFA was not significantly better than PEI.
1. Germani G, Pleguezuelo M, Gurusamy K, Meyer T, Isgrò G, Burroughs AK. Clinical outcomes of radiofrequency ablation, percutaneous alcohol and acetic acid
injection for hepatocelullar carcinoma: a meta-analysis. J Hepatol. 2010 Mar;52(3):380-8. doi: 10.1016/j.jhep.2009.12.004. Epub 2010 Jan 17.
CONCLUSIONS:
• RFA seems to be a superior ablative therapy than PEI for HCC, particularly for tumours >2 cm.
• For tumours ≤2 cm outcome benefits comparing RFA and PEI are similar.
• PAI did not differ significantly from PEI for all the outcomes evaluated.
• RFA and PAI have similar survival rates.
• PAI needs re-evaluation versus both PEI and RFA for tumours ≤2 cm.

Ablation therapies
Outcome of PEI ?
PEI Vs LR ?
PEI Vs RFA ?
Outcome of RFA ?
RFA Vs LR ?
Radiofrequency Ablation (RFA)
• The meta-analysis of several studies shows conclusively that RFA is
superior to PEI in terms of proportion dead, complete necrosis of
targeted nodule, incidence of local recurrence, and number of treatment
sessions.
• Moreover time to death and time to recurrence were significantly better
in pts treated with RFA.
Winner: RFA

MICROWAVE ABLATION (MWA): INTRO
 MWA Vs RFA: They differ in their MOA: RFA uses electric current, whereas MWA uses
electromagnetic energy.
 However, the principle underlying these two treatment methods is similar, in that high
temperatures are induced in localized areas to coagulate tissue.
 MWA has several advantages over RFA. The heat-sink effect, is an important disadvantage of
RFA. Consequently, the shape and size of the ablation zone in RFA may be unpredictable, and
such limitations can lead to an inadequate ablation zone.
 For MWA, the time needed for ablation is less than that required for RFA as MWA can deliver
higher temperatures in the ablation zone.
 These features of MWA lead to a more predictable ablation zone.
 Therefore, the apparent superiority of MWA over RFA has made it an alternative method to RFA,
and it may potentially be a more powerful technique than RFA.

RFA VS MWA
RFA MWA
Electric current Electromagnetic energy
Grounding pads (risk of burns due to ground pads) No grounding pads (no risk of burns)
Lower intratumoral temperatures Higher intratumoral temperatures
More peri-procedural pain Less peri-procedural pain
Unpredictable ablation zone More predictable ablation zone
Heat-sink effect Less susceptible to heat-sink effect
Single lesion can be treated Simultaneous treatment of multiple lesions
More procedural time Shorter procedural time
Less ablation volume Larger ablation volume
Similar complications and complication rate
Surgical clips or pacemaker are contraindications Surgical clips or a pacemaker not a contraindication
Modified from: Poulou LS,et al. Percutaneous microwave ablation vs radiofrequency ablation in the treatment of hepatocellular carcinoma. World J Hepatol. 2015 May
18; 7(8): 1054–1063.

MICROWAVE ABLATION (MWA)
 Indications and CIs for MWA are the same as those for RFA, apart from the size
of a lesion that can be ablated; according to most studies, MWA can treat 5-8
cm tumours[1].
 Furthermore, MWA allows simultaneous ablation of multiple tumours or even
combined resection and ablation.
1. Liang P, Yu J, Lu MD, Dong BW, Yu XL, Zhou XD, Hu B, Xie MX, Cheng W, He W, et al. Practice guidelines for ultrasound-guided percutaneous microwave ablation
for hepatic malignancy. World J Gastroenterol. 2013;19:5430–5438.

MWA: COMPLICATIONS
 In a multicentre study, 736 pts with hepatic lesions underwent MWA; the
reported rate of major complications was 2.9%.
 MWA was not proven to increase the risk of damage of vascular structures
and/or bleeding.
 Minor complications included pain, post-ablation syndrome, and asymptomatic
pleural effusions, which are usually self-limiting and do not require any further
treatment.
 With the peri-procedural mortality rate being reported to be as low as < 0.01%,
the safety of MWA was established[1].
1. Livraghi T, Meloni F, Solbiati L, Zanus G; Collaborative Italian Group using AMICA system. Complications of microwave ablation for liver tumors: results of a
multicenter study. Cardiovasc Intervent Radiol. 2012;35:868–874.

MWA: TUMOR RECURRENCE
 MWA shares a high rate of local recurrence in HCC with all other ablation modalities.
 Lee et al[1](n=26) studied MWA in tumours of 2-6 cm in diameter. All early postoperative CT
imaging showed no residual lesions; however, after a median follow-up of 14 (range, 4-26)
months. , 42% of pts experienced local tumour progression.
 As Lee et al[1] noted, high local tumour progression is a drawback of MWA and can be attributed
to the use of a large applicator (5 mm in diameter), which increases the risk of tumour puncture
and subsequent tumour seeding.
1. Lee KF, Hui JW, Cheung YS, Wong JS, Chong CN, Wong J, Yu SC, Lai PB. Surgical ablation of hepatocellular carcinoma with 2.45-GHz microwave: a critical appraisal
of treatment outcomes. Hong Kong Med J. 2012;18:85–91.

MWA: OUTCOME
 One of the largest series reporting long-term outcomes from MWA involved 288 pts treated at a
single institution over an eight year period [1].
 The mean maximum tumor diameter was 3.75 cm, and 63 % had a single lesion.
 At a mean follow-up of 31 months, only 24 pts (8 %) had local regrowth of a treated lesion, while
76 (26 %) developed new tumors elsewhere.
 Cumulative survival rates at one, three, and five years were 93, 72, and 52 percent, respectively,
and were significantly better for pts with maximum tumor size ≤4 cm as compared to larger
tumors.
1. Liang P, Dong B, Yu X, et al. Prognostic factors for survival in patients with hepatocellular carcinoma after percutaneous microwave ablation. Radiology 2005;
235:299.

 BACKGROUND: MWA has several advantages over RFA for the treatment of HCC. Aimed to
compare the efficacy and safety of MWA with those of RFA for HCC from the perspectives of
percutaneous and laparoscopic approaches.
 METHODS: PubMed/MEDLINE, Embase, the Cochrane library, and China Biology Medicine
databases were searched. Studies comparing the efficacy and safety of MWA with those of RFA in
patients with HCC were considered eligible. Complete ablation (CA), local recurrence (LR),
disease-free survival (DFS), overall survival (OS), and the major complication rate were compared
between MWA and RFA.

CHARACTERISTICS OF THE INCLUDED STUDIES

MWA can produce more uniform and larger tumor necrosis. However, these characteristics, in turn, are
associated with a theoretically increased risk of damaging neighboring organs, especially vascular and biliary
structures. A larger ablation area might account for a higher complication rate
 RESULTS: Four RCTs and 10 cohort studies were included.
 For percutaneous ablation, no significant difference was found between MWA and RFA regarding
CA, LR, DFS, OS, and the major complication rate.
 A subgroup analysis of tumors measuring ≥3 cm revealed no difference in CA and LR for
percutaneous ablation.
 For laparoscopic ablation, a significantly lower LR rate and a non-significant trend toward a
higher major complication rate were observed for the MWA group (OR 2.16, 95% CI 1.16-4.02,
p = .01 for LR; OR 0.21, 95% CI 0.04-1.03, p = .05 for major complication rate).
 CA, DFS, and OS were similar between the two groups.

CONCLUSIONS:
Percutaneous (P)-MWA had similar therapeutic effects compared with P-RFA for
HCC.
Pts undergoing laparoscopic MWA had a lower LR rate; however, their major
complication rate appeared to be higher.
The superiority of MWA over RFA remains unclear and needs to be confirmed by
high-quality evidence.

OTHER TREATMENTS
Irreversible Electroporation (IRE)
Laser-induced thermotherapy (LA)
Cryoablation (CA)
High-intensity focused ultrasound
(HIFU)

LASER ABLATION THERAPY (LA)
 It causes tissue destruction by hyperthermic coagulative necrosis.
 Using a single conventional neodymium-yttrium-aluminum-garnet (Nd-YAG) laser fiber, the
maximum diameter of the ablated lesion is 2 cm, although larger lesions can be ablated by laser
splitting with simultaneous heating of multiple probes or diffuse-tip fibers that emit the laser light
in a more diffuse fashion.[1]
 Even with these newly designed laser fibers, the limiting diameter for adequate tissue destruction
using laser currently is approx 5 cm.[2]
 The cooling effect of blood flow in nearby vessels is also a problem with laser ablation, but the
size of ablation can be significantly ↑ by eliminating portal flow using the Pringle maneuver.[1]
1. Heisterkamp J, van Hillegersberg R, Mulder PG, et al. Importance of eliminating portal flow to produce larger intrahepatic lesions with interstitial laser coagulation.
Br J Surg 1997; 84:1245–1248.
2. Christophi C, Muralidharan V. Treatment of hepatocellular carcinoma by percutaneous laser hyperthermia. J Gastroenterol Hepatol 2001; 16:548–552.

LA
 Laser ablation can be performed percutaneously, laparoscopically, or during surgery.
 A study of percutaneous laser ablation of 676 pts with liver secondaries or HCC revealed no
clinically relevant complications.[1]
 However, careful pt selection in terms of liver function is important, because liver failure and death
after laser ablation of HCC have been reported in pts with Child C cirrhosis.[2]
1. Vogl TJ, Eichler K, Straub R, et al. Laser-induced thermotherapy of malignant liver tumors: general principles, equipment, procedure, side effects, complications and
results. Eur J Ultrasound 2001; 13: 117–127.
2. Giorgio A, Tarantino L, de Stefano G, et al. Interstitial laser photocoagulation under ultrasound guidance of liver tumors: results in 104 treated patients. Eur J
Ultrasound 2000; 11:181–188.

LA: OUTCOME
 Most of the studies on laser therapy for liver tumors involved pts with metastatic disease, and few
data exist on the clinical efficacy of laser ablation for HCC.
 A study showed that PCLA induced CN in 70 (82%) of 85 HCC nodules,[1] but there were no
long-term data on survival or recurrence.
 In a small series of 8 pts with HCC treated by PCLT ,follow-up CT scan showed CN in all pts with
HCCs <4 cm but not in tumors >5 cm despite repeated treatments, and histologic examination of
two large HCCs revealed a peripheral rim of viable cells after laser therapy.[2]
1. Giorgio A, Tarantino L, de Stefano G, et al. Interstitial laser photocoagulation under ultrasound guidance of liver tumors: results in 104 treated patients. Eur J
Ultrasound 2000; 11:181–188.
2. Christophi C, Muralidharan V. Treatment of hepatocellular carcinoma by percutaneous laser hyperthermia. J Gastroenterol Hepatol 2001; 16:548–552.

LASER THERAPY: OUTCOME ?
 PURPOSE: Long-term outcome of LC pts with early HCC treated with USG-guided percutaneous
LA
 PATIENTS AND METHODS: retrospectively analyzed treatment and survival parameters of 432
cirrhotic pts with nonsurgical early HCC (single nodule < or = 4 cm or three nodules < or = 3 cm
each) who had received PLA in nine Italian centers.
1. Pacella CM, Francica G, Di Lascio FM, Arienti V, Antico E, Caspani B, Magnolfi F, Megna AS, Pretolani S, Regine R, Sponza M, Stasi R. Long-term outcome of cirrhotic
patients with early hepatocellular carcinoma treated with ultrasound-guided percutaneous laser ablation: a retrospective analysis. J Clin Oncol. 2009 Jun
1;27(16):2615-21.

LASER THERAPY: OUTCOME ?
 RESULTS: Single tumors were seen in 344 (80%) of 432 pts, and two to three nodules were seen in
88 pts (20%), for a total of 548 tumors.
 An initial complete response after PLA was observed in 338 pts (78%).
 Median OS was 47 months (95% CI, 41 to 53 months).
 The 3- and 5-year cumulative survival rates were 61% and 34%, respectively.
 In multivariate analysis, independent predictors of survival were serum albumin >3.5 g/dL (P =
.002; RR = 0.580; 95% CI, 0.409 to 0.821), the achievement of a CA (P = .001; RR = 0.517; 95% CI,
0.346 to 0.771), and age <73 years (P < .001; RR = 0.466; 95% CI, 0.320 to 0.681).
 C-P A pts had a 5-year cumulative survival rate of 41%; this figure increased up to 60% with a
median survival time of 63 mnths (95% CI, 48- 78 months) in pts with tumors < or = 2.0 cm.
1. Pacella CM, Francica G, Di Lascio FM, Arienti V, Antico E, Caspani B, Magnolfi F, Megna AS, Pretolani S, Regine R, Sponza M, Stasi R. Long-term outcome of cirrhotic patients with early
hepatocellular carcinoma treated with ultrasound-guided percutaneous laser ablation: a retrospective analysis. J Clin Oncol. 2009 Jun 1;27(16):2615-21.
CONCLUSION: This analysis confirms that a complete tumor ablation results in improved survival in patients
with nonsurgical HCC. Ideal candidates for PLA are younger pts with normal serum albumin levels and tumor
size < or = 2 cm.

LA VS RFA ; WHICH ONE IS SUPERIOR ?

LA VS RFA
 Aim: In pts with cirrhosis and small HCC, thermal ablation is currently recognized as an effective
local treatment. Among thermal procedures, RFA is the most diffusely used and is the standard
against which any new treatment should be compared.
 In retrospective studies, laser ablation (LA) resulted as safe and effective as RFA. Therefore,
performed a non-inferiority RCT comparing RFA with LA in pts with cirrhosis and HCC within Milan
criteria.
 Methods: Overall, 140 pts with 157 HCC nodules were randomly assigned to receive RFA(70) or
LA(70).
 The pEP was the proportion of complete tumor ablation (CTA).
 sEP were time to local progression (TTLP) and overall survival (OS).
1. Pacella CM, et al. Radiofrequency Ablation versus Laser Ablation for the Treatment of Small Hepatocellular Carcinoma in Cirrhosis: a Randomized Trial.Journal of
Gastroenterology and Hepatology 2015 30(3):559-565

The design of the study scheduled up to 3 ablation procedures during a 6-month period. Primary outcome
measure was CTA defined as absence of any contrast enhancement within or at the periphery of the HCC
nodule. Treatment failure was defined when imaging showed a residual nodule activity after the 3 scheduled
ablations. For these pts, TACE was recommended.
LA VS RFA
 Results: Per pt CTA rates after RFA and LA were 97.4% (95% CI, 91.0–99.3) and 95.7% (88.1–98.5),
respectively (difference =1.4%, 95% CI from −6.0% to +9.0%).
 Per nodule CTA rates for RFA and LA were 97.4% (91.0–99.3) and 96.3% (89.6–98.7), respectively
(difference =1.1%, from −5.7% to +8.1%).
 The mean TTP was comparable between RFA group (42.0 months; 95% CI, 36.83–47.3) and LA
group (46.7 months; 95% CI, 41.5–51.9) (P=.591).
 The mean OS was 42 months in both groups and survival probability at 1 and 3 years was 94%
and 89% in RFA group, and 94% and 80% in LA group.
Gastroenterology and Hepatology 2015;30(3):559-565

LA VS RFA
Conclusion: LA resulted not inferior to RFA in inducing the CP-A of HCC nodules
and therefore it should be considered as an evaluable alternative for thermal
ablation of small HCC in cirrhotic patients

DIFFERENCES BETWEEN LA VS RFA
Gastroenterology and Hepatology 30(3):559-565
RFA LA
Validation Yes ; recommended by
internationally endorsed
guidelines
No
Needle Size 17 G (1.5mm) 21 G (0.7mm) Thin and flexible needles are preferable to
reach tumors more easily and safely
No of needles 1/ less time required for the
positioning
1-4 /May be challenging for less experienced
operators
Ablation time 10-12 minutes 4-6 Minutes The time factor is relevant when multiple
ablations for large or multifocal HCC are required: in this
case the procedural time becomes considerably longer
with the use of RFA
Cost/nodule 2,000 Euros 600-1200 Euros

CRYOABLATION THERAPY (CA)
 CA has been used for the RX of liver tumors since the 1980s, with the initial experience mainly in
pts with metastatic malignancies.[1]
 Rapid freezing to subzero temperature leads to ice formation causing cellular damage by
dehydration and destruction.[1]
 The procedure is usually performed during surgery with insertion of a cryoprobe cooled with
liquid nitrogen or liquid argon into the tumor mass .Intraoperative USG provides guidance to the
placement of the cryoprobe in the liver mass, and it also provides a means of monitoring the
growth of the freeze zone to ensure an adequate margin. The growing ice ball can be seen as an
expanding hyperechoic lesion, and a margin of at least 1 cm of liver tissue around the tumor
should be frozen to ensure CTA.[2]
1. Ravikumar TS, Steele GD Jr. Hepatic cryosurgery. Surg Clin North Am 1989; 69:433–440.
2. Cuschieri A, Crosthwaite G, Shimi S, et al. Hepatic cryotherapy for liver tumors. Development and clinical evaluation of a high-efficiency insulated multineedle probe system for open and
laparoscopic use. Surg Endosc 1995; 9:483–489.

CRYOABLATION (CA)
 The ability to monitor the ablation process precisely by ultrasound is an advantage of CA over the
other currently available local ablative therapies. Although CA for liver tumor is usually performed
through laparotomy, percutaneous or laparoscopic CA has also been reported.[1-3]
 CA is most effective for tumors <5 cm, although larger tumors can be treated by multiple probes
inserted simultaneously.[1]
 The main concern of cryotherapy is its associated complications that ranged from 8% to 41%, and
the death rate ranged from 0% to 17%.[4-10]
 Specific complications of cryoablation include bleeding from cracking of liver parenchyma,
freezing injury to adjacent structures such as the colon, intrahepatic abscess, and bile duct
damage resulting in the formation of biloma or biliary fistula. [4-10]
1. References are at the end of the slides

CRYOABLATION
 A syndrome of thrombocytopenia, DIC, ARDS, and AKI after CA has been described and termed
“cryoshock phenomenon”; this has been observed most frequently after ablation of large
tumors.[1]
 Although the exact cause of this phenomenon is not certain, it may be related to the release of
cytokines such as IL-6 and TNF-alpha after large volume freezing or repeated cycles of freezing
and thawing. [1]
 Cryoshock phenomenon occurred in only 1% of patients, but it was a/with a 28% risk of
death.[1]
1. Seifert JK, Morris DL. World survey on the complications of hepatic and prostate cryotherapy. World J Surg 1999; 23:109–114.

CRYOABLATION: OUTCOME
 Only limited data are available on the survival results after cryotherapy for HCC, mostly from
small series of 8 to 12 pts with a short duration of follow-up.[1-5]
 The reported 2-year survival rate after CA of HCC was 30% to 60%.[2,4,5,6]
 The largest series of cryotherapy for HCC was reported by a Chinese group, who found a 5-year
survival rate of 37.9% among 191 pts, and a 5-year survival rate of 53.1% in a subgroup of 56 pts
with tumors <5 cm.[7] These survival results appear to be comparable with that after hepatic
resection.
 So far no study has directly compared the results of CA and LR for HCC.
 Pearson et al[8] reported local recurrence in 12 (13.6%) of 88 primary or metastatic liver tumors
treated by CA after a median follow-up of 15 months.
1. Wren SM, Coburn MM, Tan M, et al. Is cryosurgical ablation appropriate for treating hepatocellular cancer? Arch Surg 1997; 132: 599–603.
2. Adam R, Akpinar E, Johann M, et al. Place of cryosurgery in the treatment of malignant liver tumors. Ann Surg 1997; 225:39–48.
3. Crews KA, Kuhn JA, McCarty TM, et al. Cryosurgical ablation of hepatic tumors. Am J Surg 1997; 174:614–617.
4. Wong WS, Patel SC, Cruz FS, et al. Cryosurgery as a treatment for advanced-stage hepatocellular carcinoma: results, complications, and alcohol ablation. Cancer 1998; 82:1268–1278.
5. Cha C, Lee FT, Rikkers LF, et al. Rationale for the combination of cryoablation with surgical resection of hepatic tumors. J Gastrointest Surg 2001; 5:206–213.
6. Zhou XD, Tang ZY, Yu YQ, et al. Clinical evaluation of cryosurgery in the treatment of primary liver cancer: report of 60 cases. Cancer 1988; 61:1889–1892.
7. Zhou XD, Tang ZY. Management of hepatocellular carcinoma: longterm outcome in 2639 cases. Gan To Kagaku Ryoho 1997; 24(suppl 1):9–16.
8. Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg 1999; 178:592–599.

CRYOABLATION
 So far one RCT has compared cryoablation with RFA in 360 pts with HCC. No
differences were observed between the two techniques concerning OS, and
tumour-free survival. Local tumour progression was significantly lower in the
cryoablation group than the RFA group.[1]
1. Wang C, Wang H, Yang W, Hu K, Xie H, Hu K-Q, et al. Multicenter randomized controlled trial of percutaneous cryoablation vs. radiofrequency ablation in hepatocellular carcinoma. Hepatology
2015;61: 1579–1590.
SUMMARY:
Overall, current data suggest that cryotherapy is an effective local ablative therapy for unresectable HCC,
although it is associated with a relatively high complication rate.

IRREVERSIBLE ELECTROPORATION (IRE)
 IRE is a recently introduced ablation technique. It acts at the level of the cell membrane and
achieves apoptotic cell death by creating irreversible pores [1]. This effect is achieved via delivery
of ultrashort pulses of high voltage and high-intensity current [2].
 The connective tissue framework and the adjacent vital structures are not damaged & it is not
affected by the heat sink effect.
 These distinct advantages have allowed IR to use IRE for treatment of HCCs that are otherwise
candidates for curative treatment but the location renders them unfit for other ablative methods.
 A number of studies with small cohorts have already explored the safety and feasibility of IRE in
the management of HCC [3-10].
Note: References are at the end of slides

HIGH-INTENSITY FOCUSED ULTRASOUND (HIFU)ABLATION
 HIFU uses externally generated sonic waves to create a sharply delineated area of thermal energy
that destroys the target tissue. Devices for HIFU (Ablatherm, Sonablate) are approved in Europe
and elsewhere, but are investigational in the United States.
 The efficacy and safety of HIFU for primary [1-5] and recurrent HCC [6] has been predominantly
shown by one group in Hong Kong.
 The pt characteristics that are a/with good outcomes are similar to those that suggest a good
outcome from RFA and other thermal ablation methods [5,7].
 There are no comparative trials versus other forms of local ablation, and the place of HIFU in the
overall treatment schema of HCC is currently undefined.
1. Cheung TT, Fan ST, Chu FS, et al. Survival analysis of high-intensity focused ultrasound ablation in patients with small hepatocellular carcinoma. HPB (Oxford) 2013; 15:567.
2. Cheung TT, Chu FS, Jenkins CR, et al. Tolerance of high-intensity focused ultrasound ablation in patients with hepatocellular carcinoma. World J Surg 2012; 36:2420.
3. Xu G, Luo G, He L, et al. Follow-up of high-intensity focused ultrasound treatment for patients with hepatocellular carcinoma. Ultrasound Med Biol 2011; 37:1993.
4. Fukuda H, Ito R, Ohto M, et al. Treatment of small hepatocellular carcinomas with US-guided high-intensity focused ultrasound. Ultrasound Med Biol 2011; 37:1222.
5. Ng KK, Poon RT, Chan SC, et al. High-intensity focused ultrasound for hepatocellular carcinoma: a single-center experience. Ann Surg 2011; 253:981.
6. Chan AC, Cheung TT, Fan ST, et al. Survival analysis of high-intensity focused ultrasound therapy versus radiofrequency ablation in the treatment of recurrent hepatocellular carcinoma. Ann Surg 2013; 257:686.
7. Shen HP, Gong JP, Zuo GQ. Role of high-intensity focused ultrasound in treatment of hepatocellular carcinoma. Am Surg 2011; 77:1496.

WHAT DO THE GUIDELINE SAY ?
clipart from: https://www.canstockphoto.com/illustration/confused.html

MODIFIED BCLC STAGING SYSTEM AND TREATMENT
STRATEGY.

NOTES FROM: MODIFIED BCLC STAGING SYSTEM AND
TREATMENT STRATEGY.
 1.‘‘Preserved liver function” refers to Child-Pugh A without any ascites, considered conditions to
obtain optimal outcomes. This prerequisite applies to all treatment options apart from
transplantation, that is instead addressed primarily to patients with decompensated or end-stage
liver function.
 2. PS 1 refers to tumour induced (as per physician opinion) modification of performance capacity.
 3. Optimal surgical candidacy is based on a multiparametric evaluation including compensated
Child-Pugh class A liver function with MELD score <10, to be matched with grade of portal
hypertension, acceptable amount of remaining parenchyma and possibility to adopt a
laparoscopic/minimally invasive approach. The combination of the previous factors should lead
to an expected perioperative mortality <3% and morbidity <20% including a postsurgical severe
liver failure incidence <5%.

RECOMMENDATIONS FROM EASL 18
 Thermal ablation with radiofrequency is the standard of care for pts with BCLC 0 and A tumours
not suitable for surgery (evidence high; recommendation strong).
 Thermal ablation in single tumours 2 to 3 cm in size is an alternative to surgical resection based
on technical factors (location of the tumour), hepatic and extrahepatic pt conditions.
 In pts with very early stage HCC (BCLC-0) radiofrequency ablation in favourable locations can be
adopted as first-line therapy even in surgical pts (evidence moderate; recommendation strong).
 Microwave ablation showed promising results for local control and survival (evidence low). Other
ablative therapies are under investigation.
 Ethanol injection is an option in some cases where thermal ablation is not technically feasible,
especially in tumours <2 cm (evidence high; recommendation strong)

 TOPICS NOT COVERED
.ROLE OF LRT AS BRIDGING/DOWNSTAGING THERAPY/ADJUVANT THERAPY
.COMBINATION THERAPIES WITH LRT
.TACE
END OF SLIDES

REFERENCES: CRYOABLATION (CA)
1. Cuschieri A, Crosthwaite G, Shimi S, et al. Hepatic cryotherapy for liver tumors. Development and clinical evaluation of a high-efficiency insulated multineedle probe system for open and
laparoscopic use. Surg Endosc 1995; 9:483–489.
2. Lezoche E, Paganini AM, Feliciotti F, et al. Ultrasound-guided laparoscopic cryoablation of hepatic tumors: preliminary report. World J Surg 1998; 22:829–836.
3. Silverman SG, Tuncali K, Adams DF, et al. MR imaging-guided percutaneous cryotherapy of liver tumors: initial experience. Radiology 2000; 217:657–664.
4. Wren SM, Coburn MM, Tan M, et al. Is cryosurgical ablation appropriate for treating hepatocellular cancer? Arch Surg 1997; 132: 599–603.
5. Adam R, Akpinar E, Johann M, et al. Place of cryosurgery in the treatment of malignant liver tumors. Ann Surg 1997; 225:39–48.
6. Crews KA, Kuhn JA, McCarty TM, et al. Cryosurgical ablation of hepatic tumors. Am J Surg 1997; 174:614–617.
7. Zhou XD, Tang ZY. Management of hepatocellular carcinoma: longterm outcome in 2639 cases. Gan To Kagaku Ryoho 1997; 24(suppl 1):9–16.
8. Wong WS, Patel SC, Cruz FS, et al. Cryosurgery as a treatment for advanced-stage hepatocellular carcinoma: results, complications, and alcohol ablation. Cancer 1998; 82:1268–1278.
9. Pearson AS, Izzo F, Fleming RY, et al. Intraoperative radiofrequency ablation or cryoablation for hepatic malignancies. Am J Surg 1999; 178:592–599.
10. Cha C, Lee FT, Rikkers LF, et al. Rationale for the combination of cryoablation with surgical resection of hepatic tumors. J Gastrointest Surg 2001; 5:206–213.

REFERENCES TO : PERCUTANEOUS ETHANOL
ABLATION/INJECTION(PEI)
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5. Livraghi T, Giorgio A, Marin G, Salmi A, De Sio I, Bolondi L, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.
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Hepatology 1992;16:353–357.
7. Livraghi T, Giorgio A, Marin G, Salmi A, de Sio I, Bolondi L, et al. Hepatocellular carcinoma and cirrhosis in 746 patients: long-term results of percutaneous ethanol injection.
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9. Clark TW. Chemical ablation of liver cancer. Tech Vasc Interv Radiol 2007;10:58–63.
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REFERENCES: SURVIVAL RESULTS AFTER PERCUTANEOUS
ETHANOL THERAPY FOR HEPATOCELLULAR CARCINOMA
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REFERENCES: FOLLOW-UP RESULTS AFTER
RADIOFREQUENCY ABLATION (RFA) THERAPY FOR HCC
1. Rossi S, Di Stasi M, Buscarini E. Percutaneous RF interstitial thermal ablation in the treatment of hepatic cancer. AJR Am
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3. Allgaier HP, Deibert P, Zuber I, et al. Percutaneous radiofrequency interstitial thermal ablation of small hepatocellular
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4. Francica G, Marone G. Ultrasound-guided percutaneous treatment of hepatocellular carcinoma by radiofrequency
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5. Curley SA, Izzo F, Delrio P, et al. Radiofrequency ablation of unresectable primary and metastatic hepatic malignancies:
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REFERENCES: IRREVERSIBLE ELECTROPORATION (IRE)
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6. Nouso, K.; Ito, Y.; Kuwaki, K.; Kobayashi, Y.; Nakamura, S.; Ohashi, Y.; Yamamoto, K. Prognostic factors and treatment effects for hepatocellular carcinoma in Child C cirrhosis. Br.
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8. Leung, D.A.; Goin, J.E.; Sickles, C.; Raskay, B.J.; Soulen, M.C. Determinants of postembolization syndrome after hepatic chemoembolization. J. Vasc. Interv. Radiol. 2001, 12, 321–
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9. Clark, T.W. Complications of hepatic chemoembolization. Semin. Interv. Radiol. 2006, 23, 119–125.
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Patients With Hepatocellular Carcinoma and Ascites: Incidence, Risk Factors, and Prognostic Prediction. J. Clin. Gastroenterol. 2011, 45, 556–562.
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prophylactic dexamethasone for transcatheter arterial chemoembolization. Hepatology 2017.

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secondary liver malignancies. Part 1: Technical and methodologic considerations. J. Vasc. Interv. Radiol. 2006, 17, 1251–1278.
2. Salem, R.; Gabr, A.; Riaz, A.; Mora, R.; Ali, R.; Abecassis, M.; Hickey, R.; Kulik, L.; Ganger, D.; Flamm, S.; et al. Institutional decision to adopt
Y90 as primary treatment for hepatocellular carcinoma informed by a 1000-patient 15-year experience. Hepatology 2018, 68, 1429–1440.
3. Spreafico, C.; Sposito, C.; Vaiani, M.; Cascella, T.; Bhoori, S.; Morosi, C.; Lanocita, R.; Romito, R.; Chiesa, C.; Maccauro, M.; et al.
Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein
invasion. J. Hepatol. 2018, 68, 724–732.
4. Vilgrain, V.; Pereira, H.; Assenat, E.; Guiu, B.; Ilonca, A.D.; Pageaux, G.-P.; Sibert, A.; Bouattour, M.; Lebtahi, R.; Allaham, W. Efficacy and
safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable
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OVERVIEW OF LRT STRATEGIES FOR HCC(A)
Modality Technique Indication + -
RFA Ablative; thermal,
Joule effect [1]
• BCLC 0, A, B
• Tumor < 2–3 cm
• Not subcapsular/
perivascular/adjacent
to gallbladder/
diaphragm
• ↓serious AEs than LR [2]
• Tissue-sparing [1]
• Most extensively studied
ablation technique, broad
clinical experience [3]
• Reduced efficiency when
HCC is subcapsular/
perivascular/ adjacent to
GB/ diaphragm [4], />3 cm
• Higher cancer-related
mortality than LR [5]
MWA Ablative; thermal,
agitation of water
molecules and
friction
• BCLC 0, A, B
• Similar profile to RFA
• Tumor ≤ 5 cm
• Less heat sink effect and
shorter duration of therapy
than RFA [6]
• Efficient in tumor ≤ 5 cm[7]
• Reduced efficacy in tumors
>5 cm [8]
• Treatment effect varies
between different devices
[9]

OVERVIEW OF LRT STRATEGIES FOR HCC(B)
IRE Ablative, non-
thermal, electric
pulses create
irreparable
membrane pores that
cause
breakdown of
transmembrane
potential
• Perivascular locations [1]
• Applicable in peribiliary
locations (limited
evidence) [2]
• No heat sink effect
• Applicable in perivascular
locations [1]
• Preservation of the extracellular
matrix
• Increased effect in tissues with
high cellularity (e.g., tumors)
• Elevated incidence of needle
tract seeding [2]
• Insertion of several needles
necessary [2]
• Limited evidence and
experience
• Requires general anesthesia [3]
TACE chemoembolization
with doxorubicin or
cisplatin (cTACE or
with drug-eluting
beads)
• Palliative indication
• BCLC B, CP A (CP B) [4,5]
• Subsegmental TACE: Very
selectively in CP B (and
superselective TACE rarely
in CP C) [6,7]
• Higher incidence of post-
embolization syndrome
adjacent to gallbladder
[8]
• Extensively studied, safety
proven [7]
• Local tumor recurrence higher
than after LR/RFA [7]
• Elevated risk of liver failure in
cases with CP B, C [9,10] and
PVT [11]
• Post-embolization syndrome
[85], decreased by
dexamethasone [12]

OVERVIEW OF LRT STRATEGIES FOR HCC(C)
Y-90 Arterial
application of
Yttrium-90 [1]
• BCLC A-C (D) [2] • Applicable in presence of
PVT [3]
• Favorable toxicity in
comparison to Sorafenib
[4]
• Less clinical experience
than with TACE
SBRT High radiation
doses delivered
in few fractions
• CP A (and B) [5] • Excellent local control
applicable to large tumors
[6]
• ↑ risk of liver toxicity in
CP B [5]

OVERVIEW OF LRT STRATEGIES FOR HCC(D)
PEI Ethanol causes
coagulation necrosis
• Only limited role in HCC
treatment today
• Highest efficacy in HCC
<2 cm [1]
• Moderate cost, simple,
attractive for developing
regions [2]
• Feasible in cirrhosis [2]
• Well-tolerated [1]
• Heterogenous intra-tumoral
distribution, especially in the
presence of septa [1]
• Higher recurrence and inferior
survival than ablation [3,4]
• Multiple injections necessary
[5]
• Obsolete technique
HIFU USG; thermal (due to
absorption of energy)
and
non-thermal
(cavitation, boiling
bubbles) effects [6]
• Largely experimental,
investigated as bridge to
transplant in CP cirrhosis
[7]
• Selective; ablation in proximity
to large vessels feasible [8]
• Non-invasive
• Combination of HIFU and TACE
may be a more effective option
than TACE monotherapy for
HCC < 5 cm [9]
• Limited inter-costal therapeutic
windows can cause reflection
and unintended burns [6]
Future: intrapleural fluid
infusion? [10]
• Significant treatment disruption
by breathing motion—often
requires mechanical ventilation

FUTURE DIRECTIONS FOR RT IN HCC

Locoregional therapy for HCC

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