Version May 2024
INTRODUCTION — Hepatocellular carcinoma (HCC) is an aggressive tumor that frequently occurs in the setting of cirrhosis. The two factors that are most important in determining a patient's prognosis and potential treatment options are the tumor mass and the patient's hepatic reserve.
Treatment options are divided into potentially curative surgical therapies (ie, resection and orthotopic liver transplantation) and nonsurgical therapies, which can be liver-directed or systemic:
●In general, for most patients with liver-isolated HCC who are not candidates for surgical resection or liver transplantation, liver-directed therapies are preferable to systemic therapy (in the absence of extensive tumor burden or extensive portal vein tumor thrombus) because of the more favorable side effect profile. (See "Overview of treatment approaches for hepatocellular carcinoma", section on 'Ineligible for transplant, no macrovascular invasion'.)
Liver-directed nonsurgical therapies are divided into local thermal ablation, which is a preferred approach for those with one or a few relatively small tumors, and other treatments for tumors that are not amenable to local ablation. These include hepatic artery-directed therapies (ie, chemoembolization, bland embolization, hepatic arterial infusion chemotherapy, radioembolization) and radiation therapy, including stereotactic body radiotherapy.
●Patients with disease spread outside of the liver are usually considered for systemic therapy rather than liver-directed therapies. (See "Systemic treatment for advanced hepatocellular carcinoma".)
This topic review covers local thermal ablation (radiofrequency ablation, laser and microwave thermal ablation, percutaneous injection therapies, cryoablation, high-intensity focused ultrasound, and irreversible electroporation) for nonsurgical candidates with one or a few small localized HCC. Other liver-directed nonsurgical therapies (embolization, hepatic arterial infusional therapy, and radiation therapy, including stereotactic radiotherapy) are discussed elsewhere, as are resection, liver transplantation, and systemic therapy for HCC, as well as an overview of treatments for HCC. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation" and "Surgical resection of hepatocellular carcinoma" and "Liver transplantation for hepatocellular carcinoma" and "Systemic treatment for advanced hepatocellular carcinoma" and "Overview of treatment approaches for hepatocellular carcinoma".)
GENERAL APPROACH TO THE PATIENT WITH LOCALIZED DISEASE
Treatment algorithms — An algorithmic approach to the treatment of HCC is shown in the figure (algorithm 1). The suggested approach is useful for conceptualizing the various treatment options that are available for individual patients but may not be applicable in all settings.
Alternative treatment algorithms are available from other groups, such as one that is used by the Barcelona Clinic Liver Cancer group, which was updated in 2022 (figure 1) [1]. However, attempts to generate algorithmic approaches to the treatment of HCC are difficult since new treatments and indications for various treatments are evolving rapidly. Furthermore, therapeutic approaches tend to vary based on the available expertise as well as variability in the criteria for hepatic resection and orthotopic liver transplantation. These issues and a general approach to treatment of HCC are discussed in detail elsewhere. (See "Overview of treatment approaches for hepatocellular carcinoma".)
Indications for local ablation
●Child-Turcotte-Pugh class A or B – Nonsurgical liver-directed therapies are commonly accepted as the best option for patients with HCCs that are confined to the liver with no worse than Child-Turcotte-Pugh class A or B cirrhosis (table 1) who do not meet resectability or transplantation criteria and yet are candidates for a liver-directed procedure based on tumor factors and underlying liver disease. For patients who are reasonable surgical candidates, most clinicians consider surgery to be preferable to local ablation, if feasible, even for small tumors. (See "Surgical resection of hepatocellular carcinoma" and 'Versus other modalities' below.)
Despite the lack of comparative trials, for most patients with small HCCs (ie, ≤5 cm), we suggest local thermal ablation over other forms of nonsurgical local therapy (eg, embolization, radiation therapy). (See 'Versus other modalities' below.)
●Child-Turcotte-Pugh class C – Patients with Child-Turcotte-Pugh class C cirrhosis are typically treated with best supportive care, unless they are eligible for liver transplantation.
Importance of multidisciplinary care — The wide variety of treatments for HCC is offered by different specialties: surgery, hepatology, radiation oncology, medical oncology, and interventional radiology. Multidisciplinary evaluation and planning typically result in more thoroughly vetted recommendations and are less likely to result in a recommendation for a procedure for which a single provider has expertise but that may not represent the optimal therapy for an individual patient. Furthermore, multidisciplinary evaluation has been associated with increased curative treatment selection and improved survival [2,3].
The majority of patients with HCC have underlying liver disease. Patients who undergo any form of therapy for HCC are at high risk for progression to liver failure because of their underlying liver disease. Furthermore, treatment of underlying liver disease, such as hepatitis B or hepatitis C, can reduce the risk of hepatic decompensation after therapy, and also reduces the risk of HCC recurrence after potentially curative treatment [4]. Proper monitoring, assessment, and treatment of the underlying liver disease may have a major impact on longer-term survival. Comprehensive care of patients with cirrhosis includes antiviral therapy for hepatitis B and C, immunization against hepatitis A and B (if indicated), regular surveillance for HCC with abdominal imaging, and endoscopic screening and surveillance for varices. (See "Epidemiology and risk factors for hepatocellular carcinoma" and "Cirrhosis in adults: Overview of complications, general management, and prognosis" and "Management of potentially resectable hepatocellular carcinoma: Prognosis, role of neoadjuvant and adjuvant therapy, and posttreatment surveillance", section on 'Antiviral therapy' and "Hepatitis B virus: Overview of management", section on 'Patients with hepatocellular carcinoma'.)
Prognostic scoring systems to assess the severity of underlying liver disease in patients undergoing treatment for HCC are discussed in detail elsewhere. (See "Staging and prognostic factors in hepatocellular carcinoma", section on 'Staging and prognostic scoring systems'.)
ASSESSING RESPONSE TO LOCOREGIONAL THERAPIES — The antitumor effect of many nonsurgical locoregional treatment modalities for HCC is not accurately reflected by conventional bidimensional tumor measurements on radiographic studies. Accurate assessment of response following ablation requires evaluation of residual tumor enhancement after therapy as based on the American College of Radiology’s Liver Imaging Reporting and Data System (LI-RADS) treatment response algorithm after locoregional therapies for HCC (algorithm 2) [5,6]. The most important feature of the treatment response algorithm is persistent lesion contrast enhancement and washout. For some patients, the effectiveness of therapy may also be monitored by serial assay of tumor markers such as alpha fetoprotein (AFP). These same characteristics are used for early detection of residual/recurrent tumor and new areas of tumor involvement. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer".)
Assessment of treatment response after nonsurgical local therapies should be performed with multiphase, contrast-enhanced, cross-sectional imaging (computed tomography [CT] with iodinated contrast or magnetic resonance imaging [MRI] with gadolinium-based agents). MRI is the preferred imaging modality with a sensitivity and specificity for lesion detection of 88 and 94 percent, respectively [7]. As tumor enhancement characteristics post-therapy are essential in assessment for tumor viability [5], contrast should be administered unless there are contraindications. Patients with iodinated contrast allergies should be routed to MRI and those with gadolinium allergies to CT. Pre-existing kidney impairment is not considered a contraindication for contrast-enhanced MRI [8]. For patients who cannot obtain a good quality MRI (eg, claustrophobia, inability to hold breath), a good quality CT might be preferred.
We recommend dynamic (contrast-enhanced) cross-sectional imaging with either CT or MRI four to six weeks after nonsurgical locoregional therapy for HCC (unless radioembolization was undertaken, for which we delay the first assessment until three months), then continued monitoring for recurrent or new disease every three months for, at least, the first year. Thereafter, cross-sectional imaging could be performed every six months. When MRI is performed, and using the LI-RADS treatment response algorithm, tumors are categorized as viable, nonviable, or equivocal (algorithm 2) [5,9]. The absence of contrast uptake within the tumor reflects nonviable tumor, while the persistence of contrast uptake indicates persistent disease, referred to as viable. If a tumor has enhancement atypical for treatment, it is deemed equivocal. Recurrence of tumor in the treated area (or elsewhere) is signaled by the reappearance of vascular enhancement or nodular, mass-like, or thick irregular tissue in or along the treated lesion. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer", section on 'Response after locoregional therapy'.)
After two years with no evidence of disease recurrence, we revert back to standard HCC surveillance with cross-sectional imaging and AFP assay every six months. The use of ultrasound in this situation is controversial, and many believe that the risk remains sufficiently high that periodic cross-sectional imaging should be continued beyond two years, particularly as costs of cross-sectional imaging have decreased over time. (See "Surveillance for hepatocellular carcinoma in adults", section on 'Summary and recommendations'.)
EFFICACY AND COMPLICATIONS OF VARIOUS APPROACHES — Several techniques are available, and the choice of one or the other is more often based on institutional expertise and preference rather than on differences in efficacy.
RFA
Patient selection — For most patients with Child-Turcotte-Pugh class A or B cirrhosis (table 1) who do not meet resectability or transplantation criteria for HCC and yet are candidates for a liver-directed procedure, we recommend radiofrequency ablation (RFA) or microwave ablation (MWA) rather than other ablation approaches, such as percutaneous ethanol injection (PEI). (See 'Versus other modalities' below.)
Although there is no absolute tumor size beyond which RFA/MWA should not be considered, the best outcomes are in patients with one or two lesions <4 cm. For appropriately selected patients with small tumors, RFA/MWA provides long-term local control for most, with the possibility of long-term disease-free survival. RFA/MWA has also been used as "bridging" therapy in patients awaiting liver transplantation to reduce the rate of dropout because of tumor progression. For patients who are reasonable surgical candidates, most clinicians consider surgery to be preferable to RFA/MWA, if feasible, even for small tumors. (See 'Versus other modalities' below.)
RFA relies on a needle electrode to deliver a high-frequency alternating current from the tip of the electrode into the tissue surrounding that electrode. As the ions within the tissue attempt to follow the change in direction of the alternating current, their movement results in frictional heating of the tissue. As the temperature within the tissue becomes elevated beyond 60ºC, cells begin to die, resulting in a region of necrosis surrounding the electrode [10].
RFA/MWA is most often used for patients who do not meet resectability or transplantation criteria for HCC and yet are candidates for a liver-directed procedure based on the presence of an HCC ≤5 cm that is confined to the liver [11]. Percutaneous RFA/MWA is also an effective alternative to repeat hepatectomy for treating a small recurrent HCC in the liver following partial hepatectomy [12-14]. (See "Management of potentially resectable hepatocellular carcinoma: Prognosis, role of neoadjuvant and adjuvant therapy, and posttreatment surveillance", section on 'Management of relapsed disease'.)
RFA/MWA is also an appropriate "bridging" therapy for patients awaiting liver transplantation to reduce the rate of dropout because of tumor progression. The use of RFA/MWA in this setting or in an attempt to downstage an individual patient whose HCC is beyond the usual transplantation criteria (referred to as neoadjuvant or "downstaging" therapy) is discussed elsewhere. (See "Liver transplantation for hepatocellular carcinoma", section on 'Bridging therapy' and "Liver transplantation for hepatocellular carcinoma", section on 'Downstaging through neoadjuvant locoregional therapy'.)
Many clinicians, including the authors of this topic, restrict RFA to cirrhotic patients of Child-Turcotte-Pugh class A or B severity only (table 1). We avoid thermal ablation for a tumor near major blood vessels (due to the heat sink effect) or in the liver hilum near major bile ducts. An ablative margin of at least 5 mm is associated with best local tumor control [15].
Some have been reluctant to perform RFA in patients with subcapsular tumors, since needle track seeding was observed in 4 of 32 patients in one series, all of whom had tumors ≤1 cm from the hepatic capsule [16]. However, a cooled-tip electrode was used in these patients, which may have permitted viable tumor cells to survive the procedure. Some published data support the safety and efficacy of RFA in appropriately selected patients with subscapular tumors [17,18].
Percutaneous RFA/MWA may be avoided for treatment of lesions that are adjacent to the diaphragm, gallbladder, or bowel for fear of diaphragmatic injury [19] or intestinal perforation. However, insulating adjacent tissues from the thermal process can be accomplished using a laparoscopic or open (laparotomy) approach to RFA [20]. (See 'Results' below and 'Adverse effects' below.)
Technique — A needle electrode is advanced into the tumor via a percutaneous, laparoscopic, or open (laparotomy) route. There are no randomized trials, and there is no consensus as to the best approach [20,21]. However, a meta-analysis of uncontrolled data on 5224 tumors treated with RFA concluded that treatment approach was a significant independent factor for local control, with the open approach providing superior local control [22]. However, this analysis was limited by the various types of electrodes and techniques used in the studies. Others conclude that the percutaneous approach is preferred for smaller (≤3 cm) tumors that are accessible percutaneously and appropriately situated, because of similar tumor control and less morbidity as compared with the open approach [23]. (See 'Adverse effects' below.)
In the United States, most patients are treated by interventional radiologists using an image-guided percutaneous approach.
Using ultrasound to guide placement, the needle electrode is advanced into the area of the tumor to be treated. Once the tines have been extended or deployed into the tissue, the needle electrode is attached to a radiofrequency generator and treatment is performed.
RFA/MWA can predictably produce an ablation area of 3 to 4 cm at a single application [24]. Tumors >3 cm often require more than one deployment of the needle electrode. In one series of 1000 RFA procedures (2140 nodules) in 664 patients, tumor sizes were 2, 2.1 to 5, and >5 cm in 200, 424, and 40 patients, respectively [13]. All nodules were ablated completely, and the mean number of electrode insertions according to tumor size was 1.5, 2.3, 4.2, and 11.7 times for nodules <2, 2.1 to 3, 3.1 to 5, and >5 cm, respectively.
It is difficult to reliably destroy tumors ≥5 cm in diameter with current RFA and MWA devices. Newer equipment that can produce larger zones of ablation is currently under investigation.
Postablation imaging — Where available, immediate pre- and postablation ultrasonographic dynamic color flow imaging using microbubble contrast agents can be helpful in detecting areas where flow persists and incomplete tumor destruction is possible. This area of the tumor can immediately be treated again during the same ablation session.
Following treatment, follow-up imaging is necessary to assess the RFA/MWA treatment result and to monitor the ablated tissue over time. The term "ablation zone" refers to the area of coagulative necrosis created by the RFA procedure. The area should encompass the treated tumor and a circumferential margin of approximately 5 to 10 mm around the tumor [25]. Peri-ablation edema may be seen as a sharply marginated, low-attenuation rim on unenhanced computed tomography (CT) and as a subtle hyperintense rim on T2-weighted magnetic resonance imaging (MRI).
For most patients we prefer MRI over contrast-enhanced CT for postablation imaging. On postprocedure MRI studies a well-demarcated ablation zone with a lack of contrast enhancement suggests no viable remaining tissue and is scored as Liver Imaging Reporting and Data System (LI-RADS) nonviable in the LI-RADS MRI treatment response algorithm (algorithm 2) [25]. A lack of contrast enhancement constitutes MRI LI-RADS nonviable tumor (algorithm 2). (See 'Assessing response to locoregional therapies' above.)
The radiographic appearance evolves over time. In the first three to six months, a thin rind of enhancing peripheral hepatic tissue may be seen. Over time, the RFA-induced coagulation forms fibrous tissue and scar tissue that gradually shrinks over a period of 6 to 12 months. The scar is well marginated and does not enhance with contrast on follow-up radiographic imaging.
By contrast, residual (or recurrent) tumor appears as an eccentric, irregular, peripheral, arterially enhancing soft tissue nodule. On MRI, a focal, eccentric, nodular, moderately hyperintense focus on T2-weighted images, in contrast to the hypointense signal of the coagulated ablation zone, with corresponding arterial enhancement on T1-weighted images and washout on delayed images is suggestive of viable tumor [5,26]. (See "Assessment of tumor response in patients receiving systemic and nonsurgical locoregional treatment of hepatocellular cancer", section on 'Imaging appearance of treated HCC'.)
Results — In contemporary series, complete radiographic response rates (ie, complete necrosis) following RFA are 90 to 99 percent for tumors <5 cm, with the highest and most consistent response rates for lesions ≤3 cm [27-34]. Complete necrosis rates are lower for larger lesions [13,35-39].
In addition to size, local efficacy is also affected by the proximity of the lesion to large blood vessels (≥3 mm). In a histologic study of explanted livers from 24 patients with HCC undergoing RFA prior to liver transplantation, the rates of complete necrosis for tumors in nonperivascular and perivascular locations were 88 and 47 percent, respectively [40]. It is speculated that blood flow in these large abutting vessels carries heat away from the lesions, known as the "heat sink" phenomenon.
Post-therapy local recurrence rates are variable, ranging from 3 to 29 percent at three years and 3 to 32 percent at five years [27-34]. The presence of a major blood vessel in the vicinity of the ablated tumor is associated with higher rates of local relapse [31,34].
Long-term survival is possible, as illustrated by data from several large retrospective series and randomized trials comparing RFA with PEI:
●Reported three- and five-year survival rates following RFA for patients fulfilling the Milan transplantation criteria (a single tumor <5 cm; or three or fewer tumors, each ≤3 cm) range from 67 to 91 percent and from 40 to 77 percent, respectively [28,29,34,41,42].
●As expected, long-term outcomes are better in patients with smaller lesions [13,43,44]. In one series of 302 patients, the three-year survival rates for lesions ≤2, 2.1 to 5, and >5 cm were 91, 74, and 59 percent, respectively [13]. Long-term outcomes are also better in patients with underlying Child-Turcotte-Pugh class A rather than class B cirrhosis (table 2).
Retreatment may be feasible and result in long-term disease control in selected patients with a localized intrahepatic recurrence [29]. However, local recurrences are uncommon in the hands of experienced clinicians treating small tumors, and distant recurrences predominate, especially if patients are followed over a long period of time. This was shown in an analysis of 5- and 10-year survival following RFA in a Japanese series of 1170 patients with HCC, the majority of whom fulfilled Milan criteria [27]. Five- and 10-year survival rates were 60 and 27 percent, respectively. While the 5- and 10-year local progression rates were only 3 percent each, the distant recurrence rates were 75 and 81 percent, respectively.
Versus other modalities
●Versus surgery – For patients who are reasonable surgical candidates most clinicians consider surgery to be preferable rather than nonsurgical ablation, even for small tumors. Long-term survival can be achieved in 40 percent or more with limited surgical resection. Although it has been difficult to show a benefit in terms of overall survival, randomized trials and meta-analyses have concluded that five-year relapse-free survival and local recurrence rates both favored surgery. This subject is addressed in detail elsewhere. (See "Overview of treatment approaches for hepatocellular carcinoma", section on 'Resection versus ablation'.)
●Versus PEI – Multiple prospective randomized trials and several meta-analyses support the superiority of RFA over percutaneous ethanol injection (PEI) [45-49]. In the most recent meta-analysis of randomized trials comparing RFA with PEI, mortality at maximal follow-up was higher in the PEI group (hazard ratio [HR] 1.49, 95% CI 1.12-2.79), and there was no difference in the frequency of reported adverse effects [46]. Although RFA requires fewer treatment sessions, its main drawback is higher cost.
In modern practice, at least in the United States, PEI is not usually recommended if other local ablative techniques are available. PEI is uncomfortable and requires more treatment sessions than RFA or MWA; in addition, it can be difficult to visualize the limits of the lesion on ultrasound because of the bubbles formed during the alcohol injection.
However, PEI appears to be as effective as RFA for small tumors, costs less, and requires a minimal amount of equipment. It is still used in some institutions to treat small HCCs in patients who are not suitable candidates for surgery, particularly in difficult locations that are unsuitable for percutaneous RFA, such as adjacent to the gallbladder, hepatic hilum, abutting the diaphragm and heart, or major vasculature, and in resource-limited settings. (See 'Percutaneous ethanol or acetic acid injection' below.)
●Versus SBRT – Stereotactic body radiation therapy (SBRT) is a technique in which a single (sometimes called stereotactic radiosurgery) or limited number of high-dose radiation therapy fractions (typically three to six) are delivered to a small, precisely defined target through the use of multiple, nonparallel radiation beams. The beams converge on the target lesion, minimizing radiation exposure to the adjacent normal tissue. This targeting allows treatment in either a single or limited number of dose fractions.
Experience with SBRT for primary liver tumors is increasing. Overall local tumor control rates two to three years following SBRT for HCC range from 68 to 95 percent. Although randomized trials have not been conducted, at least one analysis from the National Cancer Database suggests that treatment with RFA yields superior survival compared with SBRT [50]. Overall, 3684 patients received RFA and 296 had SBRT; after propensity matching, five-year overall survival was 29.8 percent in the RFA group (95% CI 24.5-35.3 percent), compared with 19.3 percent (95% CI 13.5-25.9 percent) in the SBRT group. SBRT for HCC is discussed in detail elsewhere. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'Stereotactic body radiation therapy'.)
RFA plus TACE — The majority of the blood supply to an HCC is derived from the hepatic artery rather than the portal vein. This has led to the development of techniques designed to eliminate the tumor's blood supply by particle embolization and/or to directly infuse cytotoxic chemotherapy into the branch of the hepatic artery that feeds the tumor. The majority of the published experience is with transarterial chemoembolization (TACE), in which transarterial embolization is combined with prior injection into the hepatic artery of chemotherapeutic agents, with or without lipiodol. TACE is an accepted treatment for patients with large unresectable or multiple HCCs that are not suitable for resection or local ablation. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'TACE and bland particle embolization'.)
Combining local ablation treatments, such as radiofrequency ablation (RFA), with TACE can theoretically overcome the limitations of either TACE or ablation when used alone, and combined approaches are often recommended for intermediate-size tumors (ie, 3 to 5 cm) when local ablation is feasible. These data are presented in detail separately. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation".)
Adverse effects — Although RFA is relatively well tolerated, severe and potentially fatal complications can arise. Major complications develop in 2.2 to 11 percent, and the procedural mortality rate is 0.1 to 0.8 percent [51-54].
As an example, in one series of 312 patients undergoing 350 procedures (226 percutaneous and the remainder intraoperative), there were five attributable deaths (one each from liver failure and colon perforation, three from portal vein thrombosis) [51]. Portal vein thrombosis was significantly more common in cirrhotic (2 of 5) compared with noncirrhotic livers (0 of 54) after intraoperative RFA performed during a Pringle maneuver. The 37 nonfatal serious complications (incidence 11 percent) included:
●Liver abscess in seven patients, which developed in all three patients with a bilioenteric anastomosis compared with less than 2 percent of the others (see "Pyogenic liver abscess"). At most institutions, patients undergoing RFA receive a single prophylactic dose of intravenous antibiotics, unless there is a bilioenteric anastomosis or indwelling biliary stent, in which case the duration of antibiotics is extended to 24 hours of intravenous antibiotics and one week of oral antibiotics.
●Pleural effusion and skin burns in five patients each.
●Hypoxemia during treatment in four patients.
●Pneumothorax in three patients.
●Subcapsular hematoma in two patients.
●Acute renal insufficiency, hemoperitoneum, and needle tract seeding in one patient each.
Several of the more serious complications arise from placing the probe too close to the diaphragm or an intra-abdominal organ, resulting in ablation of that organ, with the accompanying complications of perforation, diaphragmatic injury, or pulmonary damage. This can be avoided by using an open or laparoscopic approach to treatment, with or without the use of hydrodissection to push the gastrointestinal tract and diaphragm away from the tumor to allow for RFA (see 'Technique' above). Injury to biliary structures may result in biloma and bile duct strictures [55].
A self-limited postablation syndrome similar to that occurring after hepatic chemoembolization has been reported, with fever, malaise, chills, right upper quadrant pain, nausea, and elevated transaminase levels. Although not as well studied, the incidence seems to be lower after RFA (36 percent in one report [56]) than after chemoembolization.
MWA — Where local expertise is available, microwave ablation (MWA) is an acceptable alternative to RFA. One advantage of MWA over RFA is the ability to perform multiple ablations simultaneously; there is no comparable RFA system with this capacity. Experience with this approach is increasing, and the technique is now preferred over RFA at many institutions. Although targeting hepatic lesions for MWA can be challenging, a novel three-dimensional electromagnetic guidance system has been developed that might improve the accuracy of intraoperative antenna placement [57].
MWA relies on a needle antenna from which electromagnetic microwaves are emitted to agitate water molecules, thereby producing friction and heat. Among the advantages of MWA over RFA are that multiple ablations can be performed simultaneously, and that its efficacy is not reduced by electrical impedance that is created with tissue charring. MWA has been used for hepatic tumor ablation in China and Japan for years; there is less experience in the United States, although this is likely changing.
●Efficacy and complications – One advantage of MWA over RFA is the ability to perform multiple ablations simultaneously; there is no comparable RFA system with the capacity to drive multiple electrically dependent electrodes. Another advantage is that MWA takes only 20 to 30 percent of the time that is required for RFA. Other advantages include higher intratumoral temperatures, larger tumoral ablation volumes, faster tumor ablation, and lower heat sink response [58].
The reported complete response rates with MWA for HCC are between 89 and 95 percent in most series, local recurrence rates are 4 to 22 percent at two to three years, and three-year survival rates range from 51 to 81 percent [39,59-72].
One of the largest series reporting long-term outcomes from MWA involved 288 patients treated at a single institution over an eight-year period [59]. The mean maximum tumor diameter was 3.75 cm, and 63 percent had a single lesion. At a mean follow-up of 31 months, only 24 patients (8 percent) had local regrowth of a treated lesion, while 76 (26 percent) 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 patients with a maximum tumor size ≤4 cm as compared with larger tumors.
Comparative data with other ablation methods, especially RFA, are limited and discordant:
•A meta-analysis of a single randomized trial [46,73-76] plus six retrospective reports concluded that there was similar efficacy (complete response rate, local recurrence rate, overall survival) between the two procedures but that local recurrence rates were significantly less for MWA as compared with RFA for larger lesions (>2 cm) [76].
•The better outcomes with MWA for larger lesions could not be confirmed in a later randomized trial comparing RFA with MWA in 203 patients with HCC and no more than three nodules, none >5 cm [75]. The one-, three-, and five-year local tumor progression rates were 1.1, 4.3, and 11.4 percent with MWA versus 2.1, 5.8, and 19.7 percent with RFA, and these values were not significantly different (p = 0.11). There were no significant differences in subsets of tumors, including those ≤3.0 cm, those 3.1 to 5.0 cm, and those in "risky" locations (ie, adjacent to blood vessels or the gallbladder). The one-, three-, and five-year overall survival rates with MWA were 96, 82, and 67 versus 96, 81, and 73 percent with RFA.
The major complication rates were 3.4 percent for MWA versus 2.5 percent for RFA, including needle seeding, gastrointestinal bleeding, and pleural effusion. MWA needed significantly fewer sessions, had shorter applicator puncture and ablation durations, and had lower hospitalization costs than RFA.
•A network meta-analysis of six randomized trials directly comparing RFA and MWA for very early HCC, MWA was not significantly worse than RFA for overall survival at one year (HR 0.76, 95% CI 0.22-2.42) or at three years (HR 0.98, 95% CI 0.65-1.48);the higher local recurrence rates at one year with MWA did not reach the level of statistical significance (HR 1.43, 95% CI 0.64-3.63) [77].
The most detailed comparison of treatment-related toxicity comes from a randomized phase II trial comparing both approaches in 202 patients with HCC [78]. Overall the rate of any treatment-related complications was twofold higher after RFA (15 of 105 versus 7 of 98), but the majority were grade 1 or 2 (12 of 15 versus 5 of 7) and there were few grade 3 (pneumothorax requiring intervention, umbilical vein lesion requiring surveillance, intrahepatic segmental necrosis) or 4 (arterial bleeding requiring embolization) events in either group (3 of 15 versus 2 of 7).
Laser ablation — Percutaneous laser ablation uses light energy that is delivered into the tumor tissue through a directly inserted laser fiber. Laser ablation can induce complete necrosis in a high proportion of HCCs <4 cm, and it may provide successful palliation of portal vein occlusion due to tumor thrombus [79-84].
●Efficacy – Much of the published experience is from a single Italian institution [79,80,82]. In the largest series from this group, 432 cirrhotic patients with nonsurgical small primary HCCs (a single nodule ≤4 cm; or no more than three nodules, ≤3 cm each) underwent ultrasound-guided laser ablation using a 5-watt laser coupled to one to four fibers and directed percutaneously into the liver through a 21-gauge needle, with tumors treated for 6 to 12 minutes per session [80]. At one month postprocedure, 338 patients had a complete initial response (78 percent), as defined by lack of contrast enhancement on triple-phase CT. At a median follow-up of 36 months, 67 patients had a local recurrence in the vicinity of the primary tumor (20 percent), and the median disease-free survival was 26 months. Three- and five-year cumulative survival rates were 61 and 34 percent, respectively.
●Complications – Complications of laser ablation were addressed in a report of 520 patients treated at nine Italian centers with 1004 laser ablation procedures [85]. There were four deaths (mortality rate 0.8 percent), and the major and minor complication rates (reported as the incidence in the total number of sessions rather than patients) were 1.5 and 6.2 percent, respectively.
Although these results seem promising, there is no evidence to support greater efficacy or safety with laser ablation compared with either RFA or MWA [46]. Furthermore, the equipment is expensive and not widely available. This approach is mainly used in Europe.
HIFU ablation — High-intensity focused ultrasound (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 they are investigational in the United States.
The place of HIFU in the overall treatment schema of HCC is currently undefined. The efficacy and safety of HIFU for primary [86-90] and recurrent HCC [91] have been predominantly shown by one group in Hong Kong. The patient characteristics that are associated with good outcomes are similar to those that suggest good outcomes from RFA and other thermal ablation methods [90,92]. However, there are no comparative trials versus other forms of local ablation.
Cryoablation — Although cryoablation may be used intraoperatively in conjunction with hepatic resection, we suggest RFA or MWA rather than cryoablation for nonsurgical treatment of primary liver tumors. These approaches are technically easier and may be associated with lower local recurrence and complication rates.
Cryoablation is a form of in situ tumor ablation in which subfreezing temperatures are delivered by penetrating the hepatic surface with a cryoprobe and cooling tissues to the point of irreversible tissue destruction. One or more probes are placed centrally within a lesion, and liquid nitrogen or argon gas (creating cooling by the Joule-Thomson effect) is circulated through the probe. The cryolesion (termed "ice ball") is hypoechoic and can be visualized and monitored by intraoperative ultrasound [93]. Normally, two freeze-thaw cycles are used, attempting to achieve a 5 to 10 mm ablation margin of hepatic parenchyma surrounding the tumor. Cryoablation may be performed percutaneously or under direct vision in the operating room.
Postprocedure, patients must be monitored with complete blood counts, a coagulation profile, electrolytes, blood urea nitrogen, serum creatinine, and myoglobin every eight hours. Alkaline hydration is used as necessary until the urine is free of myoglobin [94-96]. (See "Prevention and treatment of heme pigment-induced acute kidney injury (including rhabdomyolysis)", section on 'Treatment'.)
●Results – Outcome data are difficult to interpret since almost all reports combine patients treated with cryoablation alone and those treated as an adjunct to surgery (in patients undergoing resection of an HCC who have close or positive resection margins). The vast majority of data are from nonrandomized trials and retrospective reports [97-100].
In the largest series of 866 patients with HCC within Milan transplantation criteria (a single tumor <5 cm; or three or fewer tumors, each ≤3 cm) in which cryotherapy was used as a sole treatment modality, after a median follow-up of 31 months, 502 patients (60 percent) recurred (local recurrence 12 percent, distant intrahepatic recurrence 45 percent, extrahepatic recurrence 0.8 percent) [101]. The five-year survival was 60 percent.
Most institutions have abandoned cryotherapy for treating primary liver tumors in favor of other low-morbidity ablative procedures, such as RFA, which is technically easier to do and, in many (but not all [102]) reports, may be associated with lower local recurrence (2 versus 12 to 14 percent, respectively) and complication rates (3 versus 41 percent, respectively) [35]. At least one randomized trial comparing both procedures suggests similar long-term overall and tumor-free survival rates with both RFA and cryoablation [102]. A similar conclusion was reached in a network meta-analysis of treatments for very early HCC that included these randomized trials and several other observational studies [77].
Although cryoablation has been viewed as an alternative to RFA for tumor sites with a higher potential for local thermal complications, few centers continue to perform cryotherapy for liver tumors, and they are predominantly in China.
●Complications – Most of the reported complications are from series of intraoperative use of cryoablation. Reported complications include cracking of the ice ball or liver surface fracture leading to hemorrhage, coagulopathy and cardiac arrhythmia [94-96,103], thrombocytopenia [96,104], biliary fistula [104], bleeding [95,104,105], electrolyte disturbances [105], iatrogenic probe injury, cryogenic shock [94,103], intrahepatic or subphrenic abscess [106,107], pleural effusion [95,96,104], myoglobinuria [108], and acute renal failure. In a collective review, the overall complication rate was 50 percent [109]. Procedure-related mortality is 0 to 4 percent in most series, although rates as high as 17 percent are reported [95,101,109,110].
IRE — Where available, irreversible electroporation (IRE) represents a nonthermal ablation method that may be preferred over thermal ablation techniques for lesions in a "risky" location, such as adjacent to blood vessels. However, in our view, larger series of patients with longer follow-up durations are needed to assess the long-term efficacy of this ablation method before it can be applied with the same confidence as RFA or MWA.
IRE is a method of tumor ablation that does not use thermal effect to induce cell death. The basic principle is to create irreversible pores in the cell membranes by subjecting them to a series of high-voltage and high-intensity electrical pulses of short duration (70 to 100 microseconds) [111,112]. This results in apoptosis of the tumor cells with preservation of the extracellular matrix within the liver as well as the surrounding blood vessels and bile ducts. Compared with thermal ablation methods, the heat sink effect of local blood flow is no longer a limitation for IRE. However, general anesthesia is required, with muscular blockade in patients with sinusoidal cardiac rhythm as IRE is synchronized with the heartbeat to avoid cardiac arrhythmia [113]. IRE is contraindicated in patients with cardiac arrhythmias and pacemakers.
Few data are available for treatment of HCC; most series that describe IRE treatment for liver tumors include both primary liver tumors (HCC, cholangiocarcinoma) and hepatic metastases, and most suffer from small numbers of HCC patients and short follow-up [114-117]. The best data for HCC come from a retrospective single-center case series of 75 tumors treated with IRE in 58 patients [118]. Patients were largely deemed poor candidates for other ablation procedures because of tumor location or poor general condition. Overall, 58 (77 percent), 67 (89 percent), and 69 (92 percent) of the 75 treated tumors were completely ablated after one, two, or three IRE procedures, respectively. At a median follow-up of nine months, the 6- and 12-month local progression-free survival rates were 87 and 70 percent, respectively. Complications occurred in 11 patients and included three patients with liver failure in the setting of Child-Turcotte-Pugh class B cirrhosis; one died.
Percutaneous ethanol or acetic acid injection — Multiple prospective randomized trials and meta-analyses support the superiority of RFA over percutaneous injection of either ethanol or acetic acid, and in modern practice, at least in the United States, percutaneous ethanol or acetic acid injection is not usually recommended if other local ablative techniques (especially RFA and MWA) are available. PEI is uncomfortable and requires more treatment sessions than RFA; in addition, it can be difficult to visualize the limits of the lesion on ultrasound because of the bubbles formed during the alcohol injection. However, there may still be a role for PEI in resource-limited settings, or if ablation is technically challenging or cannot be performed safely.
Injection of 95 percent ethanol directly into a tumor through a needle (PEI) can induce local coagulation necrosis and a fibrous reaction, as well as thrombosis of tumor microvasculature and tissue ischemia [119-121]. To achieve complete devitalization of the tumor, multiple treatment sessions are usually needed.
Before the advent of RFA, PEI was the most widely accepted minimally invasive method for treating HCC. Randomized trials and at least two meta-analyses have demonstrated superior results with RFA rather than PEI, and RFA has replaced PEI in most places. (See 'RFA' above.)
Patient selection
●Tumor size – In modern practice, at least in the United States, PEI is not usually recommended for small HCCs if other local ablative techniques (especially RFA) are available. (See 'RFA' above and "Surgical resection of hepatocellular carcinoma".)
However, PEI appears to be as effective as RFA for small tumors [122-124], costs less, and requires a minimal amount of equipment. It is still used in some institutions to treat small HCCs in patients who are not suitable candidates for surgery, particularly in difficult locations that are unsuitable for percutaneous RFA, such as adjacent to the gallbladder, hepatic hilum, abutting the diaphragm and heart, or major vasculature [125]. (See 'Versus other modalities' above.)
Local response is closely related to tumor size (see 'Results' below). PEI is generally not recommended for tumors >5 cm because of high local recurrence rates [126-129]. However, local recurrence rates as high as 38 percent have been reported even for tumors up to 3 cm in diameter [129]. Because of these high recurrence rates, the procedural pain, and the need for multiple treatments, we typically consider PEI only in patients with solitary tumors <2 cm in diameter who lack the hepatic reserve to withstand resection and for whom RFA is not feasible (eg, patients with a tumor near major blood vessels [due to the heat sink effect], near other organs [due to fear of collateral injury with thermal treatment], or in the liver hilum near major bile ducts). Lesions in the dome of the liver should not be considered for this approach.
●Contraindications – Candidates for PEI must have tumors whose volume is less than 30 percent of the total liver volume. PEI is contraindicated in patients with extrahepatic disease, portal vein thrombosis, Child-Turcotte-Pugh class C cirrhosis with a prothrombin time >40 percent of normal, or a platelet count ≤40,000/microL [120,130].
Technique — For smaller lesions, PEI can be performed as an outpatient procedure with multiple separate injection sessions (eg, twice-weekly injection of 1 to 8 mL ethanol for a total of 4 to 12 sessions). However, it is painful. Alternatively, an inpatient "one shot" technique with the patient under general anesthesia may be employed, in which approximately 60 to 150 mL of ethanol is delivered via multiple injections over 30 minutes [127,131].
Conventionally, PEI is performed using a fine needle with an end hole, which does not ensure diffusion of the ethanol to the entire tumor, especially if ≥3 cm in size. A new device (the Quadra-Fuse needle, Rex Medical) has been developed that is an 18-gauge puncture needle with three retractable prongs, each with four terminal side holes that can be deployed up to 5 cm. These features facilitate even distribution of the ethanol within the tumor. Initial reports using this device are promising, with complete response rates of 67 and 84 percent, respectively, in two small series of 12 and 20 patients with HCC [132,133]. However, long-term outcomes have not yet been reported.
Results — Local response is closely related to tumor size. A complete response can be obtained in 90 to 100 percent of tumors <2 cm, in 70 to 80 percent of tumors <3 cm, but only in 50 to 60 percent for larger lesions [119,134,135]. Local recurrence rates range from 10 to 33 percent in tumors smaller than 3 cm and from 44 to 50 percent in larger tumors [129,136-138].
Percutaneous injection of acetic acid may have similar efficacy to but fewer side effects than PEI [45,139,140]. However, there is less experience with this agent, and it is not a preferred approach. The two available trials comparing percutaneous acetic acid injection with PEI are insufficient to allow conclusions as to the relative benefits and harms of either approach [141].
●Versus RFA – Multiple prospective randomized trials and several meta-analyses support the superiority of RFA over PEI [45-49]. (See 'RFA' above.)
In the most recent meta-analysis of randomized trials comparing RFA with PEI, mortality at maximal follow-up was higher in the PEI group (HR 1.49, 95% CI 1.12-2.79), and there was no difference in the frequency of reported adverse effects [46]. Although RFA requires fewer treatment sessions, its main drawback is higher cost.
On the other hand, a meta-analysis concluded that compared with RFA, percutaneous acetic acid injection was associated with significantly higher mortality at maximal follow-up (HR 1.77, 95% CI 1.12-2.79) [46].
●Versus surgery – Retrospective series suggest that for small solitary HCCs, PEI may produce survival rates that are similar to surgical resection. One study of 63 patients with a solitary HCC <4 cm found that tumor recurrence rates at two years were lower in those treated with surgery (45 versus 66 percent), but survival rates at one and four years were similar (81 and 44 percent for PEI versus 86 and 34 percent for resection) [142]. In the only randomized trial to compare PEI with resection in 160 patients with a solitary HCC up to 5 cm in diameter, there was no significant difference in either disease-free or overall survival [143].
Despite these results, most clinicians consider surgery to be preferable, if feasible, even for small tumors.
●Plus other local therapies – For small HCCs, the combination of PEI and TACE may provide better local control than PEI alone. In one trial, 52 patients with one to three HCCs measuring <3 cm were randomly assigned to PEI alone or to PEI preceded by one course of TACE (using lipiodol plus epirubicin and gelatin sponge [Gelfoam]) [144]. (See "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation".)
The cumulative detection rates for residual disease were significantly lower at one and three years with TACE plus PEI (3.7 and 19.3 percent, respectively) compared with PEI alone (34.2 and 39.3 percent, respectively). Nevertheless, the cumulative survival rates at one, three, and five years were not significantly different (100, 81, and 40 percent for TACE plus PEI and 91, 66, and 38 percent for PEI alone, respectively).
One advantage of PEI relative to thermal ablation (RFA and MWA) is that its efficacy is not limited by large vessels that create a heat sink for thermal ablation. Therefore, the combination of thermal ablation and PEI is used at times for tumors adjacent to large vessels. The tumor is thermally ablated, and the portion of the tumor adjacent to a large vessel is injected with ethanol.
Adverse effects — PEI is generally well tolerated; however, side effects such as localized pain and generalized peritoneal irritation due to ethanol leakage are common and may reduce patient compliance. Serious complications (intraperitoneal hemorrhage, liver failure, bile duct necrosis or biliary fistula, portal vein thrombosis, hepatic infarction, hypotension, or renal failure) are rare [127,136]. In one report of 270 patients with HCC treated with PEI, the incidence of major complications was only 2.2 percent, and the mortality rate was 0 percent [136]. By comparison, RFA is associated with a major complication rate of 2.2 to 11 percent and a mortality rate of 0.3 to 0.8 percent. (See 'Adverse effects' above.)
POST-TREATMENT SURVEILLANCE — Even patients who have a good response to treatment are at risk for disease recurrence and second primary HCCs. There is no consensus as to the optimal approach for post-treatment surveillance in patients undergoing locoregional therapy for HCC. Guidelines from the National Comprehensive Cancer Network suggest the following after ablation or resection [145]:
●Imaging every three to six months for two years, then annually
●Assay of serum alpha fetoprotein, if initially elevated, every three months for two years, then every six months
It is also important that patients with more advanced liver disease have proper monitoring for esophageal varices and assessment and treatment of their underlying liver disease, which may have a major impact on longer-term survival. (See 'Importance of multidisciplinary care' above.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Hepatocellular carcinoma".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Liver cancer (The Basics)")
SUMMARY AND RECOMMENDATIONS
●General approach
•Hepatocellular carcinoma (HCC) is an aggressive tumor that often occurs in the setting of chronic liver disease and cirrhosis. Disease extent and the patient's hepatic reserve dictate the therapeutic options.
•An overview of a general approach to treatment of HCC is shown in the algorithm (algorithm 1). An alternative algorithm is available from the BCLC (figure 1). Algorithmic approaches such as these are useful for conceptualizing the various treatment options that are available for individual patients, but it may not be applicable in all settings. (See "Overview of treatment approaches for hepatocellular carcinoma", section on 'Treatment algorithms'.)
•A majority of patients with HCC have underlying liver disease, and following any form of therapy for HCC, are at high risk for progression to liver failure. All patients with HCC should have proper monitoring and assessment of their underlying liver disease during treatment; multidisciplinary care improves longer-term survival. (See 'Importance of multidisciplinary care' above.)
●Indications for ablation
•Nonsurgical liver-directed therapies are commonly accepted as the best option for patients with HCCs that are confined to the liver and with no worse than Child-Turcotte-Pugh class A or B cirrhosis (table 1), who do not meet resectability or transplantation criteria and yet are candidates for a liver-directed procedure based on tumor factors and underlying liver disease.
•Although comparative trials are lacking, for most patients with a small (≤5 cm) HCC, we suggest local thermal ablation over other forms of nonsurgical local therapy (eg, embolization or stereotactic radiotherapy) (Grade 2C). (See 'Indications for local ablation' above.)
For patients who are reasonable surgical candidates, surgery is generally preferred over nonsurgical ablation, even for small tumors. (See "Overview of treatment approaches for hepatocellular carcinoma", section on 'Resection versus ablation'.)
•Patients with Child-Turcotte-Pugh class C cirrhosis are typically treated with best supportive care, unless they are eligible for liver transplantation. In such cases, local ablation may be used to control early-stage HCC in patients awaiting transplantation as a "bridging therapy" given the unpredictable length of time patients may be on the waiting list. (See "Liver transplantation for hepatocellular carcinoma", section on 'PEI, RFA, and microwave ablation'.)
●Choice of method
•Several methods are available for local ablation, including radiofrequency ablation (RFA), microwave ablation (MWA), percutaneous ethanol injection (PEI), percutaneous acetic acid injection, cryoablation, laser ablation, irreversible electroporation (IRE), and stereotactic body radiotherapy (SBRT). There is little evidence to support a "best" method for local tumor ablation, and the choice of ablation method is often based on institutional preference and local expertise rather than on differences in efficacy. (See 'Efficacy and complications of various approaches' above.)
•For most patients, where local expertise is available, we suggest RFA or MWA rather than PEI (Grade 2B). We also suggest RFA or MWA rather than SBRT or cryoablation (Grade 2C). Although there is no absolute tumor size beyond which RFA or MWA should not be considered, the best outcomes are in patients with one or two lesions <4 cm. (See 'RFA' above and 'Cryoablation' above.)
One advantage of MWA over RFA is the ability to perform multiple ablations simultaneously; there is no comparable RFA system with the capacity to drive multiple electrically dependent electrodes. Nonetheless, there is less experience with this approach than with RFA, and the technique is not as widely available. (See 'MWA' above.)
•Where available, IRE represents a nonthermal ablation method that may be preferred over other thermal ablation techniques for lesions in "risky" locations, such as adjacent to blood vessels. However, in our view, larger series of patients with longer follow-up durations are needed to assess the long-term efficacy of this ablation method before it can be applied with the same confidence as RFA or MWA. (See 'IRE' above.)
•Multiple prospective randomized trials and meta-analyses support the superiority of RFA over PEI, and in modern practice, at least in the United States, the use of percutaneous injection of ethanol or acetic acid is usually limited to settings where other local ablative techniques such as RFA or MWA are not available. There may still be a role for PEI in resource-limited settings, or if ablation is technically challenging or cannot be performed safely. (See 'Percutaneous ethanol or acetic acid injection' above.)
●Post-treatment follow-up
•Imaging follow-up after locoregional ablation therapy should be performed with multiphase contrast-enhanced computed tomography or magnetic resonance imaging (MRI). For most patients, we prefer MRI. Assessment of treatment outcomes follows the Liver Imaging Reporting and Data Systems treatment response algorithm, which is based upon contrast enhancement patterns (algorithm 2). (See 'Assessing response to locoregional therapies' above.)
•For patients with elevated serum levels of alpha fetoprotein, this marker can be useful to follow response and provide an early screening test for progression by imaging.
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