Ablation of Hepatic Lesions

Number: 0274

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses ablation of hepatic lesions.

1. Medical Necessity

   Aetna considers the following as medically necessary when the following criteria are met:

   1. Cryosurgery, microwave, or conventional tumor-puncture nonpulsed radiofrequency ablation for members with isolated colorectal cancer liver metastases or isolated hepatocellular cancer who are not candidates for open surgical resection when the selection criteria specified below are met.

      Members must fulfill all of the following criteria. Particular emphasis should be placed on criteria 2 and 3, which ensure that cryosurgery, microwave, or radiofrequency ablation is performed with curative intent.

      1. Members must either have hepatic metastases from a colorectal primary cancer or have a hepatocellular cancer; and
      2. Members must have isolated liver disease. Members with nodal or extra-hepatic systemic metastases are not considered candidates for these procedures; and
      3. All tumors in the liver, as determined by pre-operative imaging, would be potentially destroyed by cryotherapy, microwave, or radiofrequency ablation; and
      4. Because open surgical resection is the preferred treatment, members must be unacceptable open surgical candidates due to the location or extent of the liver disease or due to co-morbid conditions such that the member is unable to tolerate an open surgical resection; and
      5. Liver lesions must be 4 cm or less in diameter and occupy less than 50 % of the liver parenchyma. Lesions larger than this may not be adequately treated by these procedures.

      Aetna considers cryosurgery, microwave, or radiofrequency ablation of hepatic lesions experimental, investigational, or unproven when these criteria are not met.

   2. Cryosurgery, microwave, or conventional tumor-puncture nonpulsed radiofrequency ablation for unresectable neuroendocrine tumors metastatic to the liver;
   3. Combinational treatment of conventional tumor-puncture nonpulsed radiofrequency ablation and transcatheter arterial chemoembolization (see CPB 0268 - Liver and Other Neoplasms: Treatment Approaches) for the treatment of unresectable hepatocellular carcinoma when criteria for radiofrequency ablation for hepatocellular carcinomas above are met.

2. Experimental, Investigational, or Unproven

   The following procedures are considered experimental, investigational, or unproven because the effectiveness of these approaches has not been established (not an all-inclusive list):

   1. 3D contour simulation for microwave ablation of liver lesions;
   2. Combinational treatment of high-intensity focused ultrasound (HIFU) and transcatheter arterial chemo-embolization (TACE) for the treatment of hepatoblastoma;
   3. Cryosurgery, microwave, or radiofrequency ablation as a treatment of hepatic metastases from non-colonic primary cancers;
   4. Cryosurgical, microwave or radiofrequency ablation as a palliative treatment of either hepatic metastases from colorectal cancer or hepatocellular cancer;
   5. Electro-chemotherapy for the treatment of hepatocellular carcinoma and colorectal liver metastases. See also CPB 268 - Liver and Other Neoplasms: Treatment Approaches;
   6. Histotripsy (i.e., non-thermal ablation via acoustic energy delivery; HistoSonics, Inc.) for treatment of malignant hepatocellular tissue and for all other indications;
   7. Microwave ablation for the treatment of hepatic adenoma and hepatic hemangioma;
   8. No-touch radiofrequency ablation for the treatment of early-stage hepatocellular carcinoma;
   9. Percutaneous irreversible electroporation for the treatment of inoperable colorectal liver metastases. See CPB 0828 - Irreversible Electroporation (NanoKnife);
   10. Percutaneous magnetic resonance-guided ablation (radiofrequency or microwave) of small (less than or equal to 12 mm) hepatic malignancies;
   11. Percutaneous microwave ablation guided by contrast-enhanced and two-dimensional ultrasound for the treatment of hepatic alveolar echinococcosis;
   12. Percutaneous thermal segmentectomy for liver malignancies;
   13. Radiofrequency ablation for the treatment of giant hepatic hemangioma;
   14. Stereotactic percutaneous electrochemotherapy for the treatment of primary and secondary liver malignancies.

3. Related Policies

   • CPB 0268 - Liver and Other Neoplasms: Treatment Approaches - for electro-coagulation for the treatment of liver metastases
   • CPB 0492 - Radiofrequency Tumor Ablation
   • CPB 0828 - Irreversible Electroporation (NanoKnife)

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
CPT codes covered if selection criteria are met:
37243	Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; for tumors, organ ischemia, or infarction [covered for treatment of hepatocellular carcinomas]
47370	Laparoscopy, surgical, ablation of 1 or more liver tumor(s); radiofrequency
47380	Ablation, open, of one or more liver tumor(s); radiofrequency
47381	cryosurgical
47382	Ablation, one or more liver tumor(s), percutaneous, radiofrequency
47383	Ablation, 1 or more liver tumor(s), percutaneous, cryoablation
75894	Transcatheter therapy, embolization, any method, radiological supervision and interpretation [not covered for combinational treatment of radiofrequency ablation, high-intensity focused ultrasound and transcatheter arterial chemo-embolization for the treatment of unresectable hepatocellular carcinoma, hepatoblastoma] [covered for treatment of hepatocellular carcinomas]
CPT codes not covered for indications listed in the CPB:
Microwave ablation for hepatic hemangioma, no-touch radiofrequency ablation, Percutaneous thermal segmentectomy, Stereotactic percutaneous electrochemotherapy - no specific code
0600T	Ablation, irreversible electroporation; 1 or more tumors per organ, including imaging guidance, when performed, percutaneous
0601T	Ablation, irreversible electroporation; 1 or more tumors, including fluoroscopic and ultrasound guidance, when performed, open
0686T	Histotripsy (ie, non-thermal ablation via acoustic energy delivery) of malignant hepatocellular tissue, including image guidance
0888T	Histotripsy (ie, non-thermal ablation via acoustic energy delivery) of malignant renal tissue, including imaging guidance
0944T	New 3D contour simulation of target liver lesion(s) and margin(s) for image-guided percutaneous microwave ablation
37242	Vascular embolization or occlusion, inclusive of all radiological supervision and interpretation, intraprocedural roadmapping, and imaging guidance necessary to complete the intervention; arterial, other than hemorrhage or tumor (eg, congenital or acquired arterial malformations, arteriovenous malformations, arteriovenous fistulas, aneurysms, pseudoaneurysms)
Other CPT codes related to the CPB:
76940	Ultrasound guidance for, and monitoring of, parenchymal tissue ablation
77013	Computerized tomography guidance for, and monitoring of, parenchymal tissue ablation
77022	Magnetic resonance guidance for, and monitoring of, parenchymal tissue ablation
HCPCS codes not covered for indications listed in the CPB:
C9734	Focused ultrasound ablation/therapeutic intervention, other than uterine leiomyomata, with magnetic resonance (MR) guidance [not covered for combinational treatment of high-intensity focused ultrasound and transcatheter arterial chemo-embolization for the treatment of hepatoblastoma]
C9790	Histotripsy (ie, non-thermal ablation via acoustic energy delivery) of malignant renal tissue, including image guidance
Other HCPCS codes related to the CPB:
C1886	Catheter, extravascular tissue ablation, any modality (insertable)
ICD-10 codes covered if selection criteria are met:
B67.5	Echinococcus multilocularis infection of liver [Hepatic alveolar echinococcosis]
C18.0 - C20 [C78.7 also required]	Malignant neoplasm of colon, rectosigmoid junction and rectum [isolated with liver metastases] Secondary malignant neoplasm of liver and intrahepatic bile duct
C22.0 C22.2 - C22.8	Malignant neoplasm of liver [hepatoblastoma]
C7B.02	Secondary carcinoid tumors of liver [unresectable with liver metastases]
D01.5	Carcinoma in situ of liver, gallbladder and bile ducts [hepatocellular cancer]
ICD-10 codes not covered for indications listed in the CPB:
D13.4	Benign neoplasm of liver
D18.03	Hemangioma of intra-abdominal structures [giant hepatic hemangioma]

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Background

The liver is the most common site of distant metastasis from colorectal cancer.  About 25 % of patients with liver metastases from colorectal cancer have no other sites of metastasis and can be treated with regional therapies directed toward their liver tumors.  Based on a preponderance of uncontrolled studies for hepatic metastatic colorectal carcinoma, surgical resection offers the only potential for cure of selected patients with completely resected disease, with 5-year survival rates of 25 % to 46 %; however, the majority of patients with primary or metastatic malignancies confined to the liver are not candidates for resection because of tumor size, location, or multi-focality or inadequate functional hepatic reserve.  For the treatment of patients with non-resectable liver metastases, alternative local ablative therapeutic modalities have been developed.  For most patients with spread of metastatic colorectal cancer beyond the liver, systemic chemotherapy rather than regional therapy is a more appropriate option.

Cryotherapy is an effective and precise technique for inducing tumor necrosis, but it is currently performed via laparotomy.  Recent results suggest that ultrasound-guided radiofrequency thermal ablation may be an effective, minimally invasive technique for treating malignant hepatic tumors.  Both interventional therapeutic techniques have been shown to result in a remarkable local tumor control rate with improved survival results for patients with liver metastases from colorectal cancer.

The National Institute for Clinical Excellence (NICE, 2004) guidance on radiofrequency ablation (RFA) for the treatment of colorectal metastases to the liver stated that: "Current evidence on the safety of radiofrequency ablation of colorectal metastases in the liver appears adequate.  However, the evidence of its effect on survival is not yet adequate to support the use of this procedure without special arrangements for consent and for audit or research".  In patients who are not eligible for traditional surgery, RFA can be used to destroy liver tumors.  However, existing evidence does not conclusively support the effectiveness of RFA in improving patient survival.

The NICE guidance on cryotherapy of liver tumors concludes (NICE, 2010) that "current evidence on the safety of cryotherapy for the treatment of liver metastases appears adequate in the context of treating patients whose condition has such a poor prognosis, but the evidence on efficacy is inadequate in quality.  Therefore cryotherapy for the treatment of liver metastases should only be used with special arrangements for clinical governance, consent and audit or research."

Jungraithmayr et al (2005) stated that local ablative procedures such as cryosurgery and thermo-ablation are increasingly employed as a supplement to liver resection for the treatment of primary and secondary liver tumors.  However, it is still unclear whether the survival time can be extended through local ablative procedures.  In this prospective study (n = 19), these investigators reported operative actions, complications and long-term follow-up of patients with malignant liver tumors undergoing cryotherapy.  Subjects underwent cryotherapy due to a non-resectable malignant liver tumor (17 subjects with metastases of a colon carcinoma, and 2 subjects with a hepatocellular carcinoma).  A total of 12 patients (63.2 %) received cryotherapy only, and 7 patients (36.8 %) received a combination of resection and cryotherapy.  The median follow-up period was 23 months.  The 30-day mortality was 0 %, and the rate of major complications was 21 %.  After 1 year, 27.3 % of the patients were still recurrence-free.  The recurrence rate for all tumors treated was 58.8 %.  The median survival time for all patients was 21 months.  The 1- and 3-year survival rates were 62.5 % and 15.8 %, respectively.  The authors concluded that the mortality for cryotherapy is low, but there is a high rate of complications and long-term tumor control is insufficient.  If local ablative procedures of hepatic lesions are to be performed, not laparotomy but percutaneous, percutaneous thermoablation should be discussed as an alternative therapeutic measure.

Microwave energy can also be used to destroy liver neoplasms.  Microwave ablation destroys tumor cells by heat, resulting in localized areas of necrosis and tissue destruction.  Guidance from the National Institute for Health and Clinical Excellence (NICE, 2006) concluded that there is sufficient evidence of the safety and effectiveness of microwave ablation of hepatocellular carcinoma.  This conclusion was based upon the results of non-randomized controlled studies of microwave ablation of hepatocellular carcinoma that found similar outcomes to liver resection (Midorikawa et al, 2005), percutaneous ethanol injection (Seki et al, 1999), and radiofrequency ablation (Lu et al, 2005).  However, NICE (2007) found insufficient evidence of the safety and effectiveness of microwave ablation of colorectal cancer metastatic to the liver and other liver metastases.  One small randomized controlled clinical trial (n = 30) found similar overall and disease-free survival with liver resection and microwave ablation of liver metastases (Shibata et al, 2000).  Other uncontrolled case series reported similar results with microwave ablation of liver metastases (Liang et al, 2003; Morikawa et al, 2002).

National Comprehensive Cancer Network (NCCN, 2007) hepatocellular carcinoma guidelines state that microwave ablation, cryotherapy, RFA, and percutaneous ethanol injection may be used in the treatment of un-resectable non-metastatic hepatocellular carcinoma, for patients with non-metastatic hepatocellular carcinoma who do not agree to surgery, and to treat hepatocellular carcinoma which is local but inoperable (e.g., due to poor performance status or presence of comorbidity).  The NCCN guidelines make no distinction with respect to these different ablative methods.  The guidelines state that ablative therapy of colorectal cancer metastases to the liver using RFA or cryosurgery at the time of colon resection can also be considered when all measurable metastatic disease can be treated.

Kornprat et al (2007) examined the role of intra-operative thermoablation combined with resection in the treatment of hepatic metastasis from colorectal cancer.  Patients with colorectal hepatic metastases underwent hepatic resection combined with thermoablation, either cryosurgical ablation (CSA) or RFA.  Main outcome measures included local recurrence rates at ablation sites, overall survival, disease-free survival, and hepatic disease-free survival.  A total of 665 patients were enrolled in this study.  Of these, 39 (5.9 %) had additional intra-operative thermo-ablative procedures (19 RFA, 20 CSA).  There was 1 (3 %) post-operative death not directly associated with the ablation, and the total morbidity rate was 41 % (16 of 39).  No RFA-related complication occurred; however, 3 patients developed an abscess at cryoablation sites.  Actuarial 3-year survival was 47 % for the entire group, with a median follow-up of 21.1 months (range of 0.5 to 71.4 months).  The median disease-free survival was 12.3 months (range of 8.4 to 16.2 months).  Overall, the local in situ recurrence rate according to number of ablated tumors was 14 % for RFA and 12 % for CSA.  Tumor size correlated directly with recurrence (p = 0.02) in RFA-treated lesions.  The authors concluded that ablation combined with hepatic resection is rarely necessary or applicable.  However, in selected patients whose tumors were otherwise un-resectable, additional use of ablation allows effective clearance of disease.  In these patients with extensive bi-lobar disease, recurrence rates are high, but long-term survival is encouraging and may be improved with aggressive post-operative chemotherapy.

Siperstein et al (2007) evaluated factors affecting long-term survival of patients undergoing RFA of colorectal hepatic metastases, with attention to evolving chemotherapy regimens.  A total of 235 patients with colorectal metastases who were not candidates for resection and/or failed chemotherapy underwent laparoscopic RFA.  Pre-operative risk factors for survival and pre- and post-operative chemotherapy exposure were analyzed.  A total of 234 patients underwent 292 RFA sessions at an average of 8 months after initiation of chemotherapy.  Twenty-three percent had extra-hepatic disease pre-operatively.  Patients averaged 2.8 lesions, with a dominant diameter of 3.9 cm.  Kaplan-Meier actuarial survival was 24 months, with actual 3 and 5 years survival of 20.2 % and 18.4 %, respectively.  Median survival was improved for patients with less than or equal to 3 versus greater than 3 lesions (27 versus 17 months, p = 0.0018); dominant size less than 3 versus greater than 3 cm (28 versus 20 months, p = 0.07); chorio-embryonic antigen less than 200 versus greater than 200 ng/ml (26 versus 16 months, p = 0.003).  Presence of extra-hepatic disease (p = 0.34) or type of pre-/post-operative chemotherapy (5-FU-leucovorin versus FOLFOX/FOLFIRI versus bevacizumab) (p = 0.11) did not alter median survival.  The authors concluded that the number and dominant size of metastases, and pre-operative chorio-embryonic antigen value are strong predictors of survival.  Despite classic teaching, extra-hepatic disease did not adversely affect survival.  They stated that in this group of patients who failed chemotherapy, newer treatment regimens (pre- or post-operatively) had no survival benefit.  The actual 5-year survival of 18.4 % in these patients versus near zero survival for chemotherapy alone argues for a survival benefit of RFA.

In a review on the use of RFA for the treatment of primary and metastatic liver tumors, Garrean et al (2008) concluded that although RFA has been readily adopted into treatment paradigms, more rigorous trials are needed to solidify its place in the armamentarium of therapeutic strategies for hepatic malignancy.

In a systematic review on the current role of RFA in the management of hepatocellular carcinoma, Lau and Lai (2009) concluded that the evidence in the medical literature showed RFA was more effective than other local ablative therapies, and supported its use in the treatment of un-resectable small hepatocellular carcinoma, recurrent small hepatocellular carcinoma, and as bridging therapy before liver transplantation, and as a primary treatment in competition with partial hepatectomy for resectable small hepatocellular carcinoma.

Stang et al (2009) performed a systematic review on the clinical benefit and role of RFA as treatment of colorectal liver metastases (CLMs).  A PubMed literature search for original articles published until August 2008 was performed.  Studies with 40 patients, 18-month median follow-up and reported 3 year overall survival (OS) rates after RFA of CLM were selected for analysis.  A total of 13 clinical series and 8 non-randomized comparative studies were analyzed.  Median progression-free survival (PGS) after RFA ranged between 6 and 13 months.  Median and 5-year OS after RFA (RFA plus resection) ranged between 24 to 59 months and 18 to 40 % (36 to 46 months and 27 to 30 %).  Comparative studies indicated significantly improved OS after RFA versus chemotherapy alone, RFA plus chemotherapy versus RFA alone and up-front RFA versus RFA following second-line chemotherapy.  The authors concluded that these findings support that RFA prolongs time without toxicity and survival as an adjunct to hepatectomy and/or chemotherapy in well-selected patients, but not as an alternative to resection.

1. the efficacy of surgical hepatic resection versus RFA for resectable tumors;
2. the utility of RFA for un-resectable tumors; and
3. RFA approaches (open, laparoscopic, or percutaneous).

Evidence suggested that hepatic resection improves OS, particularly for patients with resectable tumors without extra-hepatic disease.  Careful patient and tumor selection was discussed at length in the literature.  Investigators who use RFA reported a wide variability in the 5-year survival rate (14 % to 55 %) and local tumor recurrence rate (3.6 % to 60 %).  The reported mortality rate was low (0 % to 2 %), and the major complications rate was commonly reported to be between 6 % and 9 %. Radiofrequency ablation is currently performed with all 3 approaches.  The authors concluded that there is a compelling need for more research to determine the efficacy and utility of RFA to increase local recurrence-free survival, PRS, and disease-free survival as well as OS for patients with CRHM.  Clinical trials have established that hepatic resection can improve OS for patients with resectable CRHM (Wong et al, 2010).

Guidelines on neuroendocrine tumors from the National Comprehensive Cancer Network (NCCN, 2009) stated that, for un-resectable liver metastases from carcinoid tumors and islet cell tumors, locally ablative therapy is recommended.

Furthermore, the 2010 NCCN practice guideline on "hepatobiliary cancers" stated that the 2 most commonly used methods of ablation therapy are percutaneous ethanol injection and RFA.

1. RF without stop-flow associated with the injection of diagnostic lipiodol in the case of a single nodule with a maximum diameter smaller than 3 cm;
2. RF with stop-flow of the hepatic artery associated with TACE in the case of a single nodule with a diameter greater than 3 cm; and
3. RF with stop-flow of the hepatic artery associated with TACE in the case of 2 to 3 nodules, a subdivision was made into 2 groups according to the volume: smaller or greater than 80 ml.

Ten out of 34 patients affected by HCC with a diameter smaller than 3cm, treated only with RF, demonstrated 100 % necrosis in the follow-up period, which varied between 6 and 24 months (average of 10 months).  The remaining 24 patients affected by HCC and treated with RF associated with stop-flow and TACE showed responses related to the volume of the tumor:

1. patients with a single nodule with a diameter of 3 to 5 cm showed 100 % necrosis;
2. patients affected by multi-focal HCC with a maximum of 3 nodules and/or total tumor mass smaller than 80 ml, for a total of 9 lesions, showed 95 % necrosis; and
3. patients affected by multi-focal HCC with more than 3 nodules (total mass less than 40 % of liver volume) or tumor mass greater than 80 ml, for a total of 13 lesions, showed 90 % necrosis.

In the group of patients affected by multiple nodules with volumes smaller than 80 ml, the technique did not show complete effectiveness, thus these patients cannot be considered cured.  Such aspects were even clearer in the more advanced stages.  The authors concluded that in this case study, RF proved effective with lesions up to 3 cm in diameter.  By reducing thermal dispersion, the association of the stop-flow technique with RFA, determined a greater volume of necrosis, which allows effective treatment of single nodules with a diameter of up to 5 cm and/or multiple nodules.  The association with TACE:

1. provided a way to high-light and treat lesions not recognizable through other imaging techniques;
2. increased the accumulation of lipid contrast in the tissue surrounding the lesion and in the vessels not occluded by thermal ablation in the lesions with diameters greater than 3 cm;
3. enabled further treatment of tumor residue possibly left untouched by thermal ablation in large tumors; and
4. increased the amount of lipiodol accumulated in normal tissue surrounding the lesion, made evident through the comparison of the dimensions of the nodule's blush between angiography and lipiodol computed tomography (CT).

These preliminary findings need to be validated by well-designed studies.

Peng et al (2013) compared RFA with or without TACE in the treatment of HCC.  A randomized controlled trial was conducted on 189 patients with HCC less than 7 cm at a single tertiary referral center between October 2006 and June 2009.  Patients were randomly assigned to receive TACE combined with RFA (TACE-RFA; n = 94) or RFA alone (n = 95).  The primary end point was OS.  The secondary end point was recurrence-free survival, and the tertiary end point was adverse effects.  At a follow-up of 7 to 62 months, 34 patients in the TACE-RFA group and 48 patients in the RFA group had died.  Thirty-three (35.1 %) patients and 52 (54.7 %) patients had developed recurrence in the TACE-RFA group and RFA group, respectively.  The 1-, 3-, and 4-year OS for the TACE-RFA group and the RFA group were 92.6 %, 66.6 %, and 61.8 % and 85.3 %, 59 %, and 45.0 %, respectively.  The corresponding recurrence-free survivals were 79.4 %, 60.6 %, and 54.8 % and 66.7 %, 44.2 %, and 38.9 %, respectively.  Patients in the TACE-RFA group had better OS and recurrence-free survival than patients in the RFA group (hazard ratio, 0.525; 95 % confidence intervals [CI]: 0.335 to 0.822; p = 0.002; hazard ratio, 0.575; 95 % CI: 0.374 to 0.897; p = 0.009, respectively).  There were no treatment-related deaths.  On logistic regression analyses, treatment allocation, tumor size, and tumor number were significant prognostic factors for OS, whereas treatment allocation and tumor number were significant prognostic factors for recurrence-free survival.  The authors concluded that TACE-RFA was superior to RFA alone in improving survival for patients with HCC less than 7 cm.  The main drawbacks of this study were:

1. small sample size,
2. not double-blinded,
3. single-center experience, and the results may not be generalizable, and
4. the majority of subjects had 1 or 2 lesions, and almost 50 % of them had a tumor of less than or equal to 3 cm.

In an editorial that accompanied the afore-mentioned study, Zhu and Salem (2013) stated that "Findings from this study require confirmation by others globally …. because only approximately 50 % of lesions were larger than 3 cm and there were no specification on the number of patients with lesion size from 3 to 7 cm, it remained unclear whether the benefits of TACE-RFA were only applicable to smaller lesions (i.e., less than 5 cm), as has been previously suggested.  Likewise, because 62 % to 67 % of patients enrolled onto this study had only one lesion, the relative benefits of combined TACE-RFA in patients with multifocal disease remain to be defined.  Finally, there was treatment cross-over in each arm, potentially confounding survival outcomes …. However, despite the available data on tolerability and safety, efficacy data for this combined approach is either negative or pending".

In a pilot study, Iezzi and colleagues (2013) evaluated the feasibility, safety and effectiveness of a new combined single-step therapy in patients with un-resectable multi-nodular uni-lobar HCC, with at least 1 lesion greater than 3 cm, with balloon-occluded RFA (BO-RFA) plus TACE of the main lesion and TACE of the other lesions.  The second purpose of this study was to compare the initial effects in terms of tumor necrosis of this new combined therapy with those obtained in a matched population treated with TACE alone in a single-step treatment in the authors’ center in the previous year.  This study was approved by the institutional review board, and informed consent was obtained from all patients.  A total of 10 consecutive patients with multi-nodular (2 to 6 nodules) uni-lobar un-resectable HCC and with a main target lesion of greater than 3 cm (range of 3.5 to 6 cm) not suitable for curative therapy were enrolled in this single-center multi-disciplinary pilot study.  The schedule consisted of percutaneous RFA (single 3-cm monopolar needle insertion) of the target lesion during occlusion of the hepatic artery supplying the tumor, followed by selective TACE, plus lobar TACE for other lesions (450-mg carboplatin and lipiodol plus temporary embolization with SPONGOSTAN).  Adverse events (AEs) and intra- and peri-procedural complications were clinically assessed.  Early local effectiveness was evaluated on 1-month follow-up multi-phasic CT on the basis of the Modified Response Evaluation Criteria in Solid Tumors (m-RECIST).  A separate evaluation of target lesions in terms of enhancement, necrotic diameter and presence and distribution of lipiodol uptake was also performed.  No major complications occurred.  Overall technical success, defined as complete de-vascularization of all nodules during the arterial phase, was achieved in 7 of 10 patients, with 3 cases of partial response (persistence of small hyper-vascular nodules).  When considering only target lesions, technical success was obtained in all patients, with a non-enhancing area corresponding in shape to the previously identified HCC (necrotic diameter, 3.5 to 5 cm) and with circumferential peripheral lipiodol uptake (safety margin) of at least 0.5 cm (0.5 to 1.3cm).  The authors concluded that TACE and BO-RFA, plus TACE in a single-step approach appears to be a safe and effective combined therapy for treating advanced, unresectable HCC lesions, allowing a high rate of complete local response to be achieved in large lesions also.

Wiggermann et al (2013) evaluated the reliability of ultrasound (US) elastography for delineating thermal ablation defects post- RFA by comparing lesion dimensions determined by real-time elastography (RTE) with the findings of contrast-enhanced US (CEUS).  A total of 21 malignant liver tumors were percutaneously ablated using RFA.  Color-coded elastography and CEUS were performed by 1 experienced examiner, using a 1 to 5 MHz multi-frequency convex transducer (LOGIQ E9, GE).  Lesions were examined using CEUS and RTE to assess ablation defects.  Measurements of lesions (long axis, short axis, and area) representing the same image plane used for elastography were taken during CEUS examination and compared to the measurements obtained from the elastograms.  All measurements were performed by 2 independent observers.  A statistically significant correlation in-vivo between RTE and CEUS measurements with respect to the lesion's principal axis and area (r = 0.876 long axis, r = 0.842 short axis and r = 0.889 area) was found.  Inter-rater reliability assessed with the concordance correlation coefficient was substantial for all measurements (p ≥ 0.96).  Overall, elastography slightly under-estimated the lesion size, as judged by the CEUS images.  The authors concluded that these findings support that RTE could potentially be used for the routine assessment of thermal ablation therapies.

Westwood et al (2013) stated that medical imaging techniques are important in the management of many patients with liver disease.  Unenhanced US examinations sometimes identify focal abnormalities in the liver that may require further investigation, primarily to distinguish liver cancers from benign abnormalities.  One important factor in selecting an imaging test is the ability to provide a rapid diagnosis.  Options for additional imaging investigations include CT and/or magnetic resonance imaging (MRI) and biopsy when the diagnosis remains uncertain.  Computed tomography and MRI usually require referral with associated waiting time and are sometimes contraindicated.  The use of contrast agents may improve the ability of US to distinguish between liver cancer and benign abnormalities and, because it can be performed at the same appointment as unenhanced US, more rapid diagnoses may be possible.  These investigators compared the clinical effectiveness and cost-effectiveness of CEUS using SonoVue(^®) with that of contrast-enhanced CT (CECT) and contrast-enhanced MRI (CEMRI) for the assessment of adults with focal liver lesions (FLLs) in whom previous liver imaging is inconclusive.  A total of 8 bibliographic databases including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from 2000 to September/October 2011.  Research registers and conference proceedings were also searched.  Systematic review methods followed published guidance.  Risk of bias was assessed using a modified version of the QUADAS-2 tool.  Results were stratified by clinical indication for imaging (characterization of FLLs detected on US surveillance of cirrhosis patients, detection of liver metastases, characterization of incidentally detected FLLs, assessment of treatment response).  For incidental FLLs, pooled estimates of sensitivity and specificity, with 95 % CIs, were calculated using a random-effects model.  For other clinical indications a narrative summary was used.  The cost-effectiveness of CEUS was modelled separately for the 3 main clinical applications considered [characterization of FLLs detected on US surveillance of cirrhosis patients, detection of liver metastases in patients with colorectal cancer (CRC), characterization of incidentally detected FLLs].

Of the 854 references identified, 19 (describing 18 studies) were included in the review.  Hand-searching of conference proceedings identified a further 3 studies; 20 of the 21 studies included in the systematic review were diagnostic test accuracy studies.  Studies in cirrhosis patients reported varying estimates of test performance.  There was no consistent evidence of a significant difference in performance between imaging modalities.  It was unclear whether or not CEUS alone is adequate to rule out HCC for FLLs of less than 30 mm; 1 study indicated that CEUS may be better at ruling out HCC for FLLs of 11 to 30 mm [very small FLLs (less than 10 mm) excluded].  There was no consistent evidence of a difference in test performance between imaging modalities for the detection of metastases; CEUS alone may be adequate to rule out liver metastases in CRC.  In patients with incidentally detected FLLs, the pooled estimates of sensitivity for any malignancy using CEUS and CECT were 95.1 % and 94.6 %, respectively, and the corresponding specificity estimates were 93.8 % and 93.1 % respectively.  One study comparing CEUS with CEMRI reported similar sensitivity and lower specificity for both modalities.  In the surveillance of cirrhosis, CEUS was as effective as but £379 less costly than CECT; CEMRI was £1063 more costly than CEUS and gained 0.022 quality-adjusted life years (QALYs).  In the detection of liver metastases from CRC, CEUS cost £1 more than CECT, and at a lifetime time horizon they yielded equal QALYs; CEMRI was dominated by CECT.  In the characterization of incidentally detected FLLs, CEUS was slightly more effective than CECT and CEMRI (by 0.0002 QALYs and 0.0026 QALYs, respectively) and less costly (by £52 and £131, respectively).  The authors concluded that SonoVue CEUS could provide similar diagnostic performance to other imaging modalities (CECT and CEMRI) for the assessment of FLLs.  Economic analyses indicated that CEUS was a cost-effective replacement for CEMRI.  The use of CEUS instead of CECT was considered cost-effective in the surveillance of cirrhosis and the characterization of incidentally detected FLLs, with similar costs and effects for the detection of liver metastases from CRC.  Moreover, they stated that further research is needed to compare the effects of different imaging modalities (SonoVue CEUS, CECT, CEMRI) on therapeutic planning, treatment and clinical outcomes.  Furthermore, they stated that future test accuracy studies should provide standardized definitions of a positive imaging test, and compare all 3 imaging modalities in the same patient group.

Alzaraa et al (2013) noted that the use of contrast agents (CA) with liver US has gained recently an established role for the diagnosis of various hepatic diseases due to their safety, high versatility and low costs (CEUS).  These researchers provided a state-of-the-art summary of the available evidence for their use in the characterization of focal liver lesions.  A published work search was conducted for all pre-clinical and clinical studies involving CA on hepatic US imaging.  Contrast-enhanced US increased the sensitivity for lesion detection and the specificity to differentiate between benign and malignant diseases due to the enhanced visualization of the tumor microcirculation.  Results achieved seem at least equivalent to those of spiral CT or MRI.  The association of CA with intra-operative US has changed the surgical approach in 25 % of patients and guarantees complete ablations by a single session in most of them.  The authors concluded that CEUS provides detailed information about tumor vasculature, improves the pre-operative characterization and therefore the therapeutic strategy, and can evaluate the intra-operative completeness of the ablation.

The National Comprehensive Cancer Network’s clinical practice guideline on "Hepatobiliary cancers" (Version 2.2013) states that "Diagnostic HCC imaging involves the use of one or more of the following modalities: 4-phase helical CT; 4-phase dynamic contrast-enhanced MRI; or contrast-enhanced ultrasound (CEUS) …. Liver lesions less than 1 cm should be evaluated by at least a 3-phase contrast-enhanced CT or MRI or CEUS every 3 to 6 months, with enlarging lesions evaluated according to size.  Patients with lesions stable in size should be followed with imaging every 3 to 6 months using the same imaging modality that was first used to identify the nodules".

Wang et al (2014) evaluated the effectiveness of high-intensity focused ultrasound (HIFU) combined with TACE in treating pediatric hepatoblastoma.  A total of 12 patients with initially un-resectable hepatoblastoma were enrolled in the study.  All patients received chemotherapy, TACE and HIFU ablation.  Follow-up materials were obtained in all patients.  The tumor response, survival rate and complication were analyzed.  Completely ablation was achieved in 10 patients (83.3 %), and the alpha-fetoprotein level was also decreased to normal in these patients.  The mean follow-up time was 13.3 ± 1.8 months (range of 2 to 25 months).  At the end of follow-up, 2 patients died from tumor progression, the rest 10 patients were alive.  One patient was found to have lung metastasis after HIFU and had an operation to remove the lesion.  The median survival time was 14 months, and the survival rates of 1, 2-year were 91.7 % and 83.3 %, respectively.  Complication included fever, transient impairment of hepatic function and mild malformation of rib.  The authors concluded that HIFU combined with TACE is a safe and promising method with a low rate of severe complications.  As a non-invasive approach, it may provide a novel locally therapy for patients with un-resectable hepatoblastoma.

1. HCC,
2. colorectal liver metastases,
3. neuroendocrine liver metastases, and
4. other cancers.

Independent significance of outcome variables was established with logistic regression and Cox proportional hazards models.  A total of 450 patients were treated with 473 procedures (139 HCC, 198 colorectal liver metastases, 61 neuroendocrine liver metastases, and 75 other) for a total of 875 tumors.  Median follow-up was 18 months.  Concurrent hepatectomy was performed in 178 patients (38 %), and when performed was associated with greater morbidity.  Complete ablation was confirmed for 839 of 865 tumors (97.0 %) on follow-up cross-sectional imaging (10 were un-evaluable).  A surgical approach (open, laparoscopic, or percutaneous) had no significant impact on complication rates, recurrence, or survival.  The local recurrence rate was 6.0 % overall and was highest for HCC (10.1 %, p = 0.045) and percutaneously treated lesions (14.1 %, p = 0.014).  In adjusted models, tumor size 3 cm or more predicted poorer recurrence-free survival (hazard ratio [HR]: 1.60, 95 % CI: 1.0 to -2.50, p = 0.039).  The authors concluded that in this large data set, patients with 3 cm or more tumors showed a propensity for early recurrence, regardless of histology.  Higher rates of local recurrence were noted in HCC patients, which may reflect underlying liver disease.  There were no significant differences in morbidity or survival based on the surgical approach; however, local recurrence rates were highest for percutaneously ablated tumors.

Lei et al (2014) compared the safety and effectiveness of hepatic resection and RFA for small HCCs less than 5 cm in diameter.  A total of 289 patients were diagnosed with a small HCC (a single tumor no larger than 5 cm).  Among these patients, 133 underwent hepatic resection, and 156 received RFA.  Demographic data, intra-operative data, post-operative recovery data, and the baseline characteristics of the 2 groups of patients were compared.  The incidence of post-operative complications; 1-, 3-, and 5-year survival rates; and tumor recurrence were determined.  No statistically significant differences in the baseline characteristics were noted between the 2 groups.  By contrast, operation time (p = 0.003), intra-operative blood loss (p = 0.000), and the length of post-operative hospital stay (p = 0.000) were significantly lower in the RFA group compared with the surgical resection group.  The 2 groups displayed similar post-operative complication rates (12 % or 16/133 in the liver resection group versus 8.3 % or 13/156 in the RFA group, p = 0.395).  The 1-, 3-, and 5-year OS rates of the patients in the liver resection group were 88.7 %, 78.2%, and 66.2%, respectively, whereas the rates in the RFA group were 90.4 %, 76.3 %, and 66.0 %, respectively (p = 0.722).  The 1-, 3-, and 5-year tumor-free survival rates of patients in the resection group were 87.2 %, 69.9 %, and 58.6 %, respectively, whereas the rates in the RFA group were 85.9 %, 66.0 %, and 54.5 %, respectively (p = 0.327).  In addition, among HCC patients receiving RFA, patients with tumors no greater than 3 cm in diameter exhibited no significant differences regarding OS and tumor-free survival rates compared with patients with tumors 3 to 5 cm in diameter (all p > 0.05).  The authors concluded that RFA is a safe and effective therapeutic option for small HCCs and may be a preferred choice for HCC patients with small lesions.

Hoffmann and associates (2017) evaluated the technical success, patient safety and technical effectiveness of MR-guided microwave ablation of hepatic malignancies.  Institutional review board (IRB) approval and informed patient consent were obtained.  A total of 15 patients (age of 59.8 ± 9.5 years) with 18 hepatic malignancies (7 HCC, 11 metastases) underwent MR-guided microwave ablation using a 1.5-T MR system.  Mean tumor size was 15.4 mm ± 7.7 (7 to 37 mm).  Technical success and ablation zone diameters were assessed by post-ablative MR imaging.  Technique effectiveness was assessed after 1 month.  Complications were classified according to the Common Terminology Criteria for Adverse Events (CTCAE).  Mean follow-up was 5.8  ± 2.6 (1 to 10) months.  Technical success and technique effectiveness were achieved in all lesions.  Lesions were treated using 2.5 ± 1.2 applicator positions.  Mean energy and ablation duration per tumor were 37.6 ± 21.7 (9 to 87) kJ and 24.7 ± 11.1 (7 to 49) mins, respectively.  Coagulation zone short- and long-axis diameters were 31.5 ± 10.5 (16 to 65) mm and 52.7 ± 15.4 (27 to 94) mm, respectively; 2 CTCAE-2-complications occurred (pneumothorax, pleural effusion); 7 patients developed new tumor manifestations in the untreated liver.  Local tumor progression was not observed.  The authors concluded that microwave ablation was feasible under near real-time MR guidance and provided effective treatment of hepatic malignancies in 1 session.

Weiss and colleagues (2019) stated that percutaneous tumor ablation is commonly performed using CT or US guidance, although reliable visualization of the target tumor may be challenging; MRI guidance provides more reliable visualization of target tumors and allows for real-time imaging and multi-planar capabilities, making it the modality of choice, in particular if lesions are small.  In a retrospective, case-study, these investigators examined the feasibility, technical success, and safety of percutaneous MR-guided ablation (RFA; n = 27 / micro-wave ablation [MWA]; n = 16) of small (less than or equal to 12 mm) hepatic malignancies.   In all, 45 patients (age of 61.1 ± 11.8 years) with hepatic malignancies and a lesion diameter of less than or equal to 12 mm scheduled for percutaneous MR-guided tumor ablation based on a tumor board decision were included.  A 1.5T MR system was used for planning, targeting, and monitoring.  Feasibility assessment included the detection of the target tumor, tumor delineation during MR-fluoroscopy guided targeting, and the number of attempts needed for precise applicator placement.  Technical success was defined as successful performance of the procedure including a safety margin of 5 mm.  Safety evaluation was based on procedure-related complications.  Tumor ablation (mean diameter 9.0 ± 2.1 mm) was successfully completed in 43/45 patients.  Planning imaging was conducted without a contrast agent in 79 % (n = 37).  In 64 % (n = 30), the target tumors were visible with MR-fluoroscopy.  In 6 patients (13 %), planning imaging revealed new, unexpected small lesions, which were either treated in the same session (n = 4) or changed therapy management (n = 2) due to diffuse tumor progress.  Post-procedural imaging revealed a technical success of 100 % (43/43), with no major complications.  During follow-up, no local tumor progression was observed (mean follow-up of 24.7 ± 14.0 months) although 28 % (n = 12) patients developed new hepatic lesions distant to the ablation zone.  No major complications were observed.  The authors concluded that MR-guided ablation was a feasible approach for a safe and effective treatment of small hepatic malignancies.  Level of evidence = 4.

Combinational Treatment of Radiofrequency Ablation and Transcatheter Arterial Chemo-Embolization

1. special location (located at hepatic subcapsular, portal area, next to large blood vessels or other organs) and
2. non-special location groups.

All patients underwent TACE at 1 month pre-RFA.  Follow-up imaging with enhanced CT or MRI was performed 1 month after combined treatment to evaluate the complete ablation rate in the 2 groups.  If a complete ablation was achieved, enhanced CT or MRI was performed every 1 to 3 months to evaluate the local tumor progression.  The occurrence rate of complications, complete ablation rate, local tumor progression and time to tumor progression (TTP) were compared between 2 groups.  In the special location group, a total of 24 TACE and 26 ablations were performed in 20 patients with 22 lesions while there were 18 TACE and 17 ablations in 16 patients with 17 lesions in the non-special location group.  In the special location group, 12 patients (46.2 %) suffered procedure-related complications, including a major complication (n = 1, left ventricular failure) and a minor complication (n = 11) of vascular injury (n = 6), subcapsular hemorrhage (n = 3) and arterial-portal vein fistula (n = 2); whereas only 3 patients (17.6 %) suffered a minor complication of subcapsular hemorrhage (n = 1) and arterial-portal vein fistula (n = 2) in the special location group.  The occurrence rate of complications was similar between 2 groups (p = 0.101).  The complete ablation rate after 1 month was 68.2 % (15/22) in the special location group and it was significantly higher than that of the non-special location group (100 %, p = 0.012).  In the special location group, the 6-month, 1-, 2-, 3-year local tumor progression rates were 31.8 %, 40.9 %, 45.5 %, 45.5 % versus 0, 0, 0, 5.9 % in the non-special location group, respectively.  The mean TTP of 14.4 months in the special location group was markedly shorter than that in the non-special location group (31.5 months, p = 0.001).  The authors concluded that the combined regimen of TACE and percutaneous RFA was safe and feasible for small HCC in special location; and the rate of local tumor progression was significantly higher than that of non-special location tumor.

Ni and colleagues (2013) compared RFA and TAC) with RFA monotherapy in HCC.  These investigators searched PubMed, Medline, Embase and Chinese databases (CBMdisc and Wanfang data) for randomized controlled trails (RCTs) comparing RFA plus TACE and RFA alone for treatment of HCC from January 2000 to December 2012.  The OS rate, recurrence-free survival rate, tumor progression rate, and safety were analyzed and compared.  The analysis was conducted on dichotomous outcomes and the standard meta-analytical techniques were used.  Pooled odds ratios (ORs) with 95 % CIs were calculated using either the fixed-effects or random-effects model.  For each meta-analysis, the χ(2) and I(2) tests were first calculated to assess the heterogeneity of the included trials.  For p < 0.05 and I(2) > 50 %, the assumption of homogeneity was deemed invalid, and the random-effects model was used; otherwise, data were assessed using the fixed-effects model.  All statistical analysis was conducted using Review manager (version 4.2.2.) from the Cochrane collaboration.  A total of 8 RCTs were identified as eligible for inclusion in this analysis and included 598 patients with 306 treated with RFA plus TACE and 292 with RFA alone.  Data analysis indicated that RFA plus TACE was associated a significantly higher OS rate (OR 1-year = 2.96, 95 % CI: 1.84 to 7.74, p < 0.001; OR 2-year = 3.72, 95 % CI: 1.24 to 11.16, p = 0.02; OR 3-year = 2.65, 95 % CI: 1.81 to 3.86, p < 0.001) and recurrence-free survival rate (OR 3-year = 3.00, 95 % CI: 1.75 to 5.13, p < 0.001; OR 5-year = 2.26, 95 % CI: 1.43 to 3.57, p = 0.0004) versus that of RFA alone.  The tumor progression rate in patients treated with RFA alone was higher than that of RFA plus TACE (OR = 0.60, 95 % CI: 0.42 to 0.88, p = 0.008) and there was no significant difference on major complications between 2 different kinds of treatment (OR = 1.20, 95 % CI: 0.31 to 4.62, p = 0.79).  Additionally, the meta-analysis data of subgroups revealed that the survival rate was significantly higher in patients with intermediate- and large-size HCC underwent RFA plus TACE than in those underwent RFA monotherapy; however, there was no significant difference between RFA plus TACE and RFA on survival rate for small HCC.  The authors concluded that the combination of RFA with TACE had advantages in improving OS rate, and provided better prognosis for patients with intermediate- and large-size HCC.

Cao et al (2014) evaluated the safety and effectiveness of TACE combined with RFA and TACE alone for HCC.  PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI) and Wanfang Databases were searched for RCTs and retrospective cohort studies from the establishment of the databases to January 2014.  The bibliographies of the included studies were searched, too.  After study selection, assessment, data collection and analysis were undertaken, these researchers performed a meta-analysis by using the RevMan5.2 software.  A total of 17 studies involving 1,116 patients met the inclusion criteria with 530 treated with RFA-plus-TACE and 586 with TACE alone.  The results of meta-analysis showed that the combination of TACE and RFA was obviously associated with higher 1-, 2-, and 3-year OS rates (OR 1-year = 3.98, 95 % CI: 2.87 to 5.51, p  <0.00001; OR 2-year = 3.03, 95 % CI: 2.10 to 4.38, p < 0.00001; OR 3-year = 7.02, 95 % CI: 4.14 to 11.92, p < 0.00001) than TACE alone.  The tumor complete necrosis rate in patients treated with TACE and RFA was higher than that of TACE alone (OR = 13.86, 95 % CI: 8.04 to 23.89, p < 0.00001).  And there was a significant difference in local recurrence rate between 2 different kinds of treatment (OR = 0.24, 95 % CI: 0.14 to 0.44, p < 0.00001).  Additionally, combination of TACE and RFA was associated with higher complete tumor necrosis rates than TACE mono-therapy in the treatment of HCC.  However, RFA plus TACE was found to be associated with a lower local recurrence rate than TACE monotherapy.  TACE-plus-RFA treatment was associated with a higher response rate (RR) than the TACE-alone treatment (OR = 3.90, 95 % CI: 2.37 to 6.42, p < 0.00001).  TACE-plus-RFA treatment did not differ from the TACE-alone treatment in terms of stable disease (SD) rate (OR = 0.38, 95 % CI: 0.11 to 1.26, p = 0.11).  Meta-analyses showed that the combination of RFA and TACE was associated with a significantly lower progressive disease (PD) rate (OR = 0.15, 95 % CI: 0.05 to 0.43, p = 0.0005).  The rate of AFP reducing or returning to normal in serum in RFA plus TACE group was obviously lower than TACE alone group (OR = 4.62, 95 % CI: 2.56 to 8.34, p < 0.00001).  The effect of TACE plus RFA for HCC was better than TACE mono-therapy.  The authors concluded that the combined therapy could elevate the patients' OS rate, tumor necrosis rate and the rate of AFP reducing or returning to normal in serum and decrease local recurrence rate, PD rate compared with TACE alone.

Liang et al (2015) examined the clinical application of sequential therapy with TACE and CT-guided RFA in treating HCC of different sizes.  The study included patients (n = 46) with HCC who had received TACE and RFA from November 2012 to November 2013.  Eligible patients had an Eastern Cooperative Oncology Group (ECOG) score of 0 to 1, a Child-Pugh grade of A-B, and no contradictions for TACE and/or RFA; 51 hepatic lesions of varying sizes were treated with TACE followed by RFA.  Clinical response and 1- and 2-year survival rates were assessed.  The frequency of complete and incomplete ablation following therapy was significantly different across the varying RFA pin numbers and the maximum diameter of the lesion (p ≤ 0.001).  A greater percentage (97.3 %) of lesions that were less than or equal to 3 cm in diameter were completely ablated compared with lesions that were 3 to 5 cm (88.9 %) and greater than 5 cm in diameter (20 %).  The median survival time of patients was 16.5 months, and the 1- and 2-year survival rates were 95.7 % and 69.3 %, respectively.  There were only a limited number of complications, all of which were minor.  These included hemothorax (4.3 %), abdominal hemorrhage (10.9 %), and abdominal hemorrhage with minor pneumothorax (2.2 %).  The authors concluded that the findings of this study showed that the sequential treatment with TACE and CT-guided RFA was effective and well-tolerated in patients with HCC and that the effectiveness of treatment is dependent on tumor size.

Chevallier et al (2015) noted that local tumor recurrence after thermal ablation of HCC can impact on OS and are very closely linked to partial treatment of the primary lesion or to potential microvascular invasion or satellite micro-nodules located close to the main lesion.  The diagnosis of these liver metastases close to the primary lesion on CT and MRI is difficult and their incidence, number and spread throughout the liver correlates with diameter of primary tumor.  Tumor diameter is currently the key factor to predict whether or not thermal ablation of HCC will be complete or not.  It has now been shown for mono-polar RFA that this therapy alone is sufficient to effectively treat single HCCs less than 3 cm in diameter provided that liver micro-metastases are not present.  If the HCC is greater than 3 cm in size, multi-focal or in the case of tumor recurrence, OS and recurrence-free survival results are better if mono-polar RFA is combined with hepatic TACE.

Wang et al (2016a) compared the safety and effectiveness of combined RFA and TACE with RFA alone for HCC.  Randomized controlled trial that compared the clinical or oncologic outcomes of combination therapy of TACE and RFA versus RFA for the treatment of HCC were identified through literature searches of electronic databases (PubMed, Embase, Cochrane Library, China Biology Medicine disc, China National Knowledge Infrastructure, and Google Scholar).  Hazard ratios or odds ratios with their corresponding 95 % CI were combined as the effective value to assess the summary effects.  The strength of evidence was rated by the Grading of Recommendations Assessment, Development, and Evaluation system.  A total of 6 RCTs with 534 patients were eligible for inclusion in this meta-analysis.  The meta-analysis showed that the combination of TACE and RFA is associated with a significantly longer OS (HR = 0.62, 95 % CI: 0.49 to 0.78, p < 0.001) and recurrence-free survival (HR = 0.55, 95 % CI: 0.40 to 0.76, p < 0.001) in contrast with RFA monotherapy.  The seemingly higher incidence of major complications in the combination group compared with RFA group did not reach statistical significance (OR = 1.17, 95 % CI: 0.39 to 3.55, p = 0.78).  The authors concluded that in patients with HCC, the combination of TACE and RFA is associated with significantly higher OS and recurrence-free survival, as compared with RFA monotherapy, without significant difference in major complications.

Wang et al (2016b) examined the safety and effectiveness of RFA and TACE for treatment of patients with HCC.  All eligible studies were collected from PubMed, the Cochrane Libraries and Embase.  The evaluation indices included OS rate, recurrence-free survival rate, local tumor progression rate and major complications.  All statistical analysis was performed by RevMan version 5.2 software.  There were 21 studies with 3,073 patients included in this meta-analysis.  The RFA monotherapy was associated with higher 3- and 5-year OS rates (OR 3-year = 2.33, 95 % CI: 1.34 to 4.05; OR 5-year = 2.05, 95 % CI: 1.48 to 2.85) compared with TACE alone.  The combination of RFA and TACE was associated with higher 1-, 3- and 5-year OS rates (OR 1-year = 1.94, 95 % CI: 1.28 to 2.96; OR 3-year = 1.56, 95 % CI: 1.19 to 2.04; OR 5-year = 1.53, 95 % CI: 1.13 to 2.07) compared with RFA alone.  The authors concluded that the  combination of TACE with RFA could obviously improve the short- and long-term survival rates and significantly provide a better prognosis for patients with intermediate-size HCC.  They stated that RFA was associated with a higher long-term OS rate than that of TACE-treated patients with HCC.

Furthermore, NCCN’s clinical practice guideline on "Hepatobiliary cancers" (Version 1.206) states that "The consensus of the panel is that ablation alone may be a curative treatment for tumors less than or equal to 3 cm …. Tumors between 3 and 5 cm may be treated with a combination of ablation (cryoablation, microwave, percutaneous alcohol injection, and radiofrequency) and arterially directed therapies (e.g., TACE) to prolong survival, as long as the tumor location is favorable to ablation".

Radiofrequency Ablation for the Treatment of Hepatic Hemangioma

van Tilborg and colleagues (2013) described their initial clinical experience with bipolar radiofrequency ablation (RFA) for the treatment of symptomatic giant hepatic hemangiomas.  A total of 4 consecutive patients with a large-volume, symptomatic hepatic cavernous hemangioma of greater than 10 cm were treated with bipolar RFA during laparotomy with ultrasound guidance.  Complications were carefully noted.  Clinical and radiological effectiveness were evaluated comparing baseline with 3 and 6 months follow-up of symptom assessments and upper abdominal MRI or CT.  Radiofrequency ablation was successfully performed for all 4 giant hemangiomas.  No major complications were observed.  Peri-procedural shrinking was remarkable and intermediate-term volume reduction ranged from 58 to 92 % after 6 months.  Symptom relief after 6 months was complete in 2 patients and considerable in the remaining 2 patients.  The authors concluded that preliminary results suggested intra-operative bipolar RFA to be a safe, feasible, and effective technique for treatment of giant symptomatic hepatic cavernous hemangiomas.  These preliminary findings need to be validated by well-designed studies.

Gao and co-workers (2016) evaluated the technical and clinical outcomes of using laparoscopic RFA  for treating large subcapsular hepatic hemangiomas.  These investigators retrospectively reviewed their sequential experience of treating 124 large subcapsular hepatic hemangiomas in 121 patients with laparoscopic RFA.  The mean diameter of the 124 hemangiomas was 9.1 ± 3.2 cm (5.0 to 16.0 cm); RFA was performed successfully in all patients.  There were 55 complications related to the ablation in 26 patients, including 5 of 69 (7.3 %) patients with hemangioma less than 10 cm and 21 of 52 (40.4 %) patients with hemangiomas greater than or equal to 10 cm (p < 0.001).  No injuries to abdominal viscera occurred in all the 121 patients.  According to the Dindo-Clavien classification, all the complications were minor in 26 patients (Grade I).  Out of 124 hepatic hemangiomas, 118 (95.2 %) were completely ablated, including 70 of 72 (97.2 %) lesions of less than 10 cm and 48 of 52 (92.3 %) lesions greater than or equal to 10 cm (p = 0.236).  The authors concluded that laparoscopic RFA is a safe, feasible and effective procedure for large subcapsular hepatic hemangiomas, even in the hepatic hemangiomas of greater than or equal to 10 cm.  The main drawbacks of this study included its retrospective nature, the lack of control group, the short follow-up period and the relatively small number of patients evaluated.  Feasibility for RFA was largely dependent on the operator’s technique, experience, and the instrumental equipment of the center.  Patients in this study were managed based on the treating surgeon’s perspective as well as by a team of surgeons, making the results less applicable to non-surgical clinics.  Nevertheless, these data may be helpful for clinicians who treat subcapsular hepatic hemangiomas with RFA and may also be useful as a basis for the design of future trials.  The authors stated that more long-term outcomes and prospective RCTs are needed to define the role of laparoscopic RFA in the treatment of subcapsular hepatic hemangiomas, especially in comparison to surgical resection.

Wang and colleagues (2017) stated that minimally invasive laparoscopic resection has been used recently in liver surgery for treating selected hepatic hemangiomas.  However, laparoscopic liver surgery poses the significant technical challenges and high rate of conversion.  It is controversial to treat giant hepatic hemangiomas (greater than or equal to 10.0 cm) by means of RFA, due to the low technique success rate and high incidence of ablation-related complications.  These researchers evaluated the safety and efficacy of combined laparoscopic resection with intra-tumoral RFA-induced coagulation for giant hepatic hemangiomas.  These researchers treated 2 patients with giant subcapsular hepatic hemangioma (12.0 cm and 13.1 cm in diameters, respectively) by laparoscopic resection following intra-tumoral coagulation of the tumor with RA.  Blood loss during resection was 100 ml (case 1) and 300 ml (case 2), respectively.  No blood transfusion and dialysis were needed during peri-operative period.  The 2 patients were discharged 6 days (case 1) and 12 days (case 2) after surgery without any complications, respectively.  Post-operative contrast-enhanced CT follow-up showed there was no residual tumor.  The authors concluded the findings of this study suggested that it is feasible to treat giant subcapsular hepatic hemangioma by the technique of laparoscopic resection boosted by intra-tumoral RFA-induced coagulation, which may be recommended as the alternative treatment for symptomatic enlarging giant hepatic hemangioma.  The main drawbacks of this study included its retrospective nature, small sample size (n = 2), and the short-term follow-up (9 to 14 months).

Based on their experience and on the available literature, Treska and associates (2017) defined when and what therapeutic option should be indicated in patients suffering from liver hemangioma.  In the past 5 years, 37 patients with giant hemangiomas indicated for invasive treatment were enrolled in the study.  The mean size of the hemangiomas was 67 mm (45 to 221 mm).  Multiple hemangiomas were present in 11 (29.7 %) patients.  Enucleation was performed in 15 (40.5 %), non-anatomical liver resection in 3 (8.1 %), left lobectomy in 1 (2.7 %) and exploratory laparotomy for a suspected malignant liver tumor in 2 (5.4 %) patients where malignancy was excluded based on contrast enhanced pre-operative ultrasonography.  Percutaneous trans-arterial embolization (TAE) was performed in 16 (43.2 %) patients.  There was zero mortality.  A hematoma in the resection line, with spontaneous regression was present in 2 (10.5 %) patients after the surgery; post-embolization syndrome was seen in 3 (16.7 %) patients after TAE.  Progression of the hemangioma was seen in 3 (28.8 %), regression in 6 (37.5 %) patients, and in 7 (43.8 %) patients the finding remained stable in the interval of 14 years after TAE.  The authors concluded that conservative approach could be applied in most liver hemangiomas, especially in small, asymptomatic lesions.  Liver surgery was indicated in giant symptomatic or growing hemangiomas with the diameter over 10 cm or in non-specific lesions where the pre-operative diagnosis was uncertain.  These researchers recommended enucleation as the method of choice, or non-anatomic liver resection; TAE was indicated in high-risk patients and could be repeated if the hemangioma progresses.  Moreover, they stated that the use of other methods such as RFA needs to be verified in large clinical studies.

Furthermore, an UpToDate review on "Hepatic hemangioma" (Curry and Chopra, 2018) does not mention radiofrequency ablation as a  therapeutic option for liver hemangioma.

Percutaneous Irreversible Electroporation for the Treatment of Inoperable Colorectal Liver Metastases

Schicho and colleagues (2018) stated that for colorectal liver metastases (CRLM) that are not amenable to surgery or thermal ablation, irreversible electroporation (IRE) is a novel local treatment modality and additional option.  This study was a retrospective, long-term, follow-up of patients with CRLM who underwent IRE as salvage treatment.  Of the 24 included patients, 18 (75.0 %) were men, and the median age was 57 (range of 28 to 75) years.  The mean time elapsed from diagnosis to IRE was 37.9 ± 37.3 months.  Mean OS was 26.5 months after IRE (range of 2.5 to 69.2 months) and 58.1 months after diagnosis (range of 14.8 to 180.1 months); 1-, 3-, and 5-year survival rates after initial diagnosis were 100.0 %, 79.2 %, and 41.2 %; after IRE, the respective survival rates were 79.1 %, 25.0%, and 8.3 %.  There were no statistically significant differences detected in survival after IRE with respect to gender, age, T- or N-stage at the time of diagnosis, size of metastases subject to IRE, number of hepatic lesions, or time elapsed between IRE and diagnosis.  The authors concluded that for non-resectable CRLM, long-term survival data emphasized the value of IRE as a new minimally invasive local therapeutic approach in multi-modal palliative treatment, which is currently limited to systemic or regional therapies in this setting.

The authors stated that due to the small cohort (n = 24) and retrospective study design, it was difficult to draw broad conclusions concerning the value of IRE in the treatment of secondary, inoperable liver malignancies.  With a median survival longer than standard chemotherapy regimens, IRE should be regarded as the option-of-choice for patients with inoperable liver metastases who are not suitable for thermal ablation procedures.  Moreover, they stated that further prospective randomized studies with a larger number of patients are needed to evaluate the value of IRE in the setting of CRLM; detailed analysis of additional biomarkers, such as KRAS as prognostic indicators is needed.  In light of IRE being without an alternative in selected cases, a median survival of 26.6 months after first IRE is a promising result.

Mafeld and associates (2019) noted that IRE is a non-thermal ablative option in patients unsuitable for standard thermal ablation, due to its potential to preserve collagenous structures (vessels and ducts) and a reduced susceptibility to heat sink effects.  In this series from 2 large tertiary referral hepatobiliary centers, these researchers examined the safety/outcomes of hepatic IRE.  Bi-institutional retrospective, longitudinal follow-up series of IRE for primary hepatic malignancy; [HCC (n = 20), cholangiocarcinoma (n = 3)] and secondary metastatic disease; colorectal (n = 28), neuroendocrine (n = 1), pancreatic (n = 1), breast (n = 1), GI stromal tumor (GIST, n = 1) and malignant thymoma (n = 1).  Outcome measures included procedural safety/effectiveness, time-to-progression and time-to-death.  Between 2013 and 2017, a total of 52 patients underwent percutaneous IRE of 59 liver tumors in 53 sessions.  All tumors were deemed unsuitable for thermal ablation.  Cases were performed using US or CT guidance.  A complete ablation was achieved in 75 % (n = 44) of cases with an overall complication rate of 17 % (n = 9).  Of the complete ablation group, median time-to-progression was 8 months.  At 12 months, 44 % were progression-free (95 % CI: 30 to 66 %).  These data suggested that larger lesion size (greater than 2 cm) was associated with shorter time-to-progression and there was highly significant difference with faster time-to-progression in mCRC compared with HCC.  Median survival time was 38 months.  The authors concluded that this bi-institutional review was the largest United Kingdom series of IRE and suggested this ablative technology could be an useful tool, but appeared to mainly induce local tumor control rather than cure with HCC having better outcomes than mCRC.

Wu and co-workers (2019) stated that IRE is a novel ablative technique for hepatobiliary and pancreatic cancers.  These investigators summarized the data regarding the safety and efficacy of IRE in the treatment of hepatobiliary and pancreatic cancers.  Studies were identified by searching PubMed and Embase for articles published in English from database inception through July 31, 2017.  For inclusion, each clinical study had to report morbidity and survival data on hepatobiliary and pancreatic cancers treated with IRE and contain at least 10 patients.  Studies that met these criteria were included for analysis; 2 researchers evaluated each clinical study for data extraction.  The controversial parts were resolved through discussion with seniors.  A total of 24 clinical studies were included; 14 focused on hepatic ablation with IRE comprising 437 patients with 666 lesions of different tumor types; 2 patients (0.5 %) died after the IRE procedure.  Morbidity of hepatic ablation with IRE ranged from 7 % to 35 %.  Most complications were mild; CR for hepatic tumors was reported as 57 % to 97 %.  A total of 10 studies with 455 patients focused on pancreatic IRE.  The overall mortality of IRE in pancreatic cancer was 2 %.  Overall severe morbidity of IRE in pancreatic cancer ranged from 0 % to 20 %.  The median OS after IRE ranged from 7 to 23 months.  Patients treated with IRE combined with surgical resection showed a longer OS.  The authors concluded that IRE significantly improved the prognosis of advanced hepatobiliary and pancreatic malignances, and was associated with less complications.  These researchers stated that IRE is a relatively safe and effective non-thermal ablation strategy and potentially recommended as an option for therapy of patients with hepatobiliary and pancreatic malignances.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on "Hepatobiliary cancers" (Version 1.2019) does not mention percutaneous irreversible electroporation as a therapeutic option.

Electrochemotherapy for the Treatment of Hepatocellular Carcinoma and Colorectal Cancer Liver Metastases

Electrochemotherapy is a combined use of certain chemotherapeutic drugs and electric pulses applied to the treated tumor nodule (Sersa and Miklavcic, 2008). Local application of electric pulses to the tumor increases drug delivery into cells, specifically at the site of electric pulse application. is different from irreversible electroporation, by causing cell death predominantly by the mechanism of drug-induced apoptosis.

Coletti and associates (2017) noted that electro-chemotherapy is a novel ablation technique combining chemo-therapeutic agents with reversible cell membrane electroporation.  Its application for deep-seated malignancies is under investigation.  In a pilot study, these investigators examined the feasibility, safety, and efficacy of intra-operative electro-chemotherapy for otherwise un-resectable colorectal liver metastases.  Electro-chemotherapy with bleomycin was combined with open liver resection and performed with linear or hexagonal needle electrodes according to an individualized pre-treatment plan.  The primary end-points were: feasibility, as ratio of completed to planned treatments, safety, and efficacy, as per response assessed at 30 days with MRI and according to RECIST.  The secondary end-point was OS and progression-free survival (PFS) at month 6.  A total of 9 colorectal liver metastases were treated in 5 patients with 20 electrode applications.  No intra-operative complications were observed.  At day 30, complete response was 55.5 % and SD 45.5 %.  All 5 patients reached a 6 months OS, and 4 out of 5 patients had 6 months PFS.  The authors concluded that electro-chemotherapy was a feasible and safe adjunct to open surgery for treatment of un-resectable colorectal liver metastases.  Moreover, these researchers stated that larger studies and longer follow-ups are needed to better-define its role in the treatment of secondary liver malignancies.

In a pilot study, Djokic and colleagues (2018) examined the feasibility, safety and effectiveness of electro-chemotherapy for the treatment of HCC.  Electro-chemotherapy with bleomycin was performed on 17 HCCs in 10 patients using a previously established protocol.  The procedure was performed during open surgery and the patients were followed for a median of 20.5 months.  Electro-chemotherapy was feasible for all 17 lesions, and no treatment-related AEs or major post-operative complications were observed.  The median size of the treated lesions was 24 mm (range of 8 to 41 mm), located either centrally, i.e., near the major hepatic vessels, or peripherally.  The complete response rate at 3 to 6 months was 80 % per patient and 88 % per treated lesion.  The authors concluded that electro-chemotherapy of HCC proved to be a feasible and safe treatment in all 10 patients included in this study.  These researchers stated that to examine the effectiveness of this method, longer observation period is needed; however the results at medium observation time of 20.5 months after treatment were encouraging, in 15 out of 17 lesions complete response was obtained.  They stated that electro-chemotherapy is predominantly applicable in patients with impaired liver function due to liver cirrhosis and/or with lesions where a high-risk operation is needed to achieve curative intent, given the intra/peri-operative risk for high morbidity and mortality.

Microwave Ablation of Hepatic Adenoma

Smolock and colleagues (2016) stated that MWA was used to treat 12 hepatocellular adenomas (HAs) in 6 patients (5 women and 1 man; mean age of 39.6 years).  Mean treated tumor size was 2.7 cm ± 2.0.  Tumor response was evaluated with serial cross-sectional imaging for a mean follow-up of 12.6 months ± 7.1.  Primary treatment effectiveness and local tumor control were 100 %.  There were no instances of hemorrhage, malignant transformation, new hepatic tumors, or extra-hepatic metastases.  This early experience of treatment of HAs by MWA showed it to be a safe and feasible treatment modality at short-term follow-up.  These researchers stated that continued investigation, including comparison with other treatment modalities, is needed.

Silva and associates (2019) stated that loco-regional therapy treatments for HAs are typically limited to selective hepatic arterial embolization (HAE) to control acute hemorrhage.  These investigators carried out a systematic review to analyze the utilization of HAE and ablation for non-emergent treatment of HA.  Of 209 initial search results published from 2005 to 2016, 33 full-text publications were reviewed, and 10 were selected after applying the exclusion criteria.  A total of 105 patients were included, of which 66 patients with 138 HAs underwent elective loco-regional therapy treatment.  The mean size of treated adenomas was 2.9 (range of 0.8 to 8.3) cm.  HAE was utilized in 25 patients with 58 adenomas, whereas 35 patients with 68 adenomas underwent RFA; 6 patients with 12 adenomas received MWA.  Most patients were female (89/105), and adenomas were associated with oral contraceptive use or hormonal therapies in 49 of 105 patients.  Success was reported in 115 of 138 first-time procedures, and repeat procedures were needed after 18 of 138.  Mean follow-up time was 36.4 months, with 2 complications.  The authors concluded that reports of elective loco-regional therapy for the treatment of HA were limited to case reports and small institutional series.  In the select patients treated, outcomes were acceptable, with low rates of repeat procedures or complications.  These researchers stated that the findings of this systematic review warranted further discussion and broader consideration for the treatment of HA.

Bressem and co-workers (2020) stated that MWA is a type of minimally invasive cancer therapy that uses heat to induce necrosis in solid tumors.  Inter- and post-ablational size changes can influence the accuracy of control imaging, posing a risk of incomplete ablation.  These researchers examined post-ablation three dimensional (3D) size dynamics in-vivo using CT.  A total of 10 MWA data-sets obtained in 9 healthy pigs were used.  Lesions were sub-divided along the z-axis with an additional planar sub-division into 8 sub-sections.  The volume of the sub-sections was analyzed over different time-points, subsequently color-coded and visualized in a 3D manner.  A locally weighted polynomial regression model (LOESS) was applied to describe overall size changes, and Student's t-tests were used to assess statistical significance of size changes.  The 3D analysis showed heterogeneous volume changes with multiple small changes at the lesion margins over all time-points.  The changes were pronounced at the upper and lower lesion edges and characterized by initially eccentric, opposite swelling, followed by shrinkage.  In the middle parts of the lesion, these investigators observed less dimensional variations over the different time-points.  The authors concluded that LOESS revealed a hyperbolic pattern for the volumetric changes with an initially significant volume increase of 11.6 % (111.6 % of the original volume) over the first 32 mins, followed by a continuous decrease to 96 % of the original volume (p < 0.05).

The authors stated that this study had several drawbacks.  Due to the open cavity approach, hypothermia became more threatening with duration of the experiment.  Thus, the examination was usually stopped after the last ablation before the vital parameters became unstable.  This might have resulted in a certain heterogeneity of the measurements and have reduced statistical significance due to the low numbers of measurements with 4 or more time-points.  These researchers used domestic pigs and the properties of a healthy pig’s liver in terms of heat transmission could be different from those of a human liver containing cancerous tissue.  Therefore, these findings may not be fully transferable to humans with liver tumors.  These researchers used a low-power MW generator, which could have affected not only the lesion size but also the size dynamics and these findings were therefore probably not fully transferable to other devices.  Compared to previous ex-vivo studies, the authors also had longer ablation times, probably due to a lower power output from the MW generator as well as heat dissipation due to tissue perfusion and a heat sink effect near larger vessels.  It was also possible that inflammatory processes have affected lesion dynamics, if 1 animal underwent multiple ablations. Taken together, these may have altered the volumetric changes of the lesions.  As the LOESS model did not correct for possible clustering of the data, it might not be fully generalizable.

Furthermore, UpToDate on "Hepatic adenoma" (Curry and Afdhal, 2019) does not mention microwave ablation as a therapeutic option.

Microwave Ablation for the Treatment of Hepatic Hemangioma

Li and Xing (2023) noted that the treatment of hepatic hemangioma includes surgical resection, RFA and TAE; however, complications, mortality and compromised effectiveness limit their applications.  Microwaves with effective heating generation and short ablation time become a promising treatment.  In a systematic review and meta-analyses, these investigators examined the effectiveness of MWA for the treatment of hepatic hemangioma.  They carried out a systematic literature review in PubMed.  Main outcomes were defined as hemangioma decreases in diameters and volume changes post-MWA.  Conventional random-effect meta-analysis technique was employed to analyze the pooled data, and meta-regression model was established to examine the association among factors.  A total of 9 studies with a total of 501 patients were retrieved.  The pooled estimate of mean differences (MDs) and 95 % CI of hemangioma decreases after MWA treatment in diameter and in volume change (%) were 3.009 cm and (1.856 to 4.161), and 53.169 % and (51.274 % to 55.065 %), respectively.  The pooled estimates of liver enzyme, ALT and AST, elevations were 219.905 with 95 % CI (160.860 to 278.949) and 315.679 with 95 % CI (226.961 to 404.397), respectively.  Major complications were defined as acute kidney injury (AKI), pleural effusion, diaphragmatic hernia, and jaundice that needed to be treated, and the pooled incidence was 0.017 with 95 % CI of 0.006 to 0.029.  No mortality related to MWA was reported.  Meta-regression showed ablation time was associated with pre-operative lesion size (p = 0.001).  The authors concluded that MWA was safe and effective in the treatment of hepatic hemangioma, and the findings of this study suggested that hemangioma size should be examined in future MWA pre-treatment difficulty scoring system study.

The authors stated that this study had several drawbacks.  First, the numbers of pooled studies were relatively small (n = 9), and among them most lacked comparison with a control group.  Second, few studies giving details of hemangioma locations and depth that may enhance the difficulty of treatment and affect outcomes constrain a further analysis.  Third, subgroup studies of percutaneous and laparoscopic procedure, and 2D versus 3D should also be carried out in the future when data are available. These researchers stated that further studies with larger samples sizes, control groups and detailed tumor sites would aid in improving the quality of evidence and provide more evidence to validate an optimized difficulty scoring system for the treatment of hemangioma.

Maruyama et al (2023) stated that percutaneous ablation under imaging guidance is a curative treatment that could induce complete tumor necrosis with advantages of minimal invasiveness and a low risk of complications.  Thermal ablation, which includes RFA and MWA, is a representative technique that has sufficient anti-tumor effects in cases of HCC with 3 or less lesions measuring 3 cm or less and preserved liver function.  The short- and long-term outcomes of patients are comparable with those achieved with surgical resection.  Despite their non-malignant nature, some benign liver tumors require treatment for symptoms caused by the presence of the tumor and/or continuous enlargement.  Ablation may be the treatment of choice because it has lower burden on patients than surgical treatment.  Moreover, these researchers stated that despite the limited number of studies comparing ablation and surgical treatment, ablation appeared to provide a sufficient therapeutic effect compared with open surgery, with the advantages of safety and less burden for patients.  However, difference of clinical effectiveness between RFA and MWA for hemangioma has not been fully described, as limited studies have compared the 2 methods.  In a recent study (Kong et al, 2022), MWA had a shorter ablation time, fewer hemolysis-related complications, and a shorter hospital stay.  These investigator s stated that additional studies may be needed to compare RFA and MWA, and long-term outcomes of ablation for hemangioma with cost-effectiveness.

Furthermore, an UpToDate review on “Hepatic hemangioma” (Curry and Chopra, 2022) does not mention microwave ablation as a management / therapeutic option.     

One-Lung Ventilation for Percutaneous Thermal Ablation of Liver Tumors in the Hepatic Dome

D'Amico and associates (2019) stated that although liver resection is still the best treatment for primary or metastatic hepatic lesions, a conventional surgical approach may be challenging in patients with a history of previous abdominal surgery.  These researchers presented the case of a 58-year old man with paracaval, sub-diaphragmatic, recurrent HCC; he had a history of multiple abdominal surgeries.  In select patients, percutaneous US-guided thermal ablation is a valid non-surgical alternative due to its safety, efficacy, and good tolerability.  Hepatic lesions located in the postero-superior segments, however, can be difficult to reach via a percutaneous approach.  For these cases, one-lung left-sided ventilation may be particularly helpful in blocking the right hemi-diaphragm and improving the acoustic window to the liver.  The authors presented a case of para-caval, sub-diaphragmatic, recurrent HCC in which the tumor was only reachable after one-lung left-sided ventilation that was successfully treated by percutaneous US-guided MWA.  These researchers stated that the encouraging findings of this case justify further investigation and clinical use of one-lung left-sided ventilation to achieve percutaneous ablation of hepatic dome tumors.

Long and colleagues (2020) examined the feasibility, safety and efficacy of one-lung ventilation for percutaneous thermal ablation of liver tumors in the hepatic dome.  From January 5,  2017 to April 16, 2019, a total of 64 patients who underwent US-guided thermal ablation with a total of 75 liver malignant tumors located in the hepatic dome were enrolled in the present study.  One-lung ventilation was employed to improve the acoustic window and protect the lung and diaphragm.  If the one-lung ventilation was unsuccessful, artificial pleural effusion was added.  The technical efficacy was confirmed by contrast-enhanced CT/MRI 1 month later.  After that, CT/MRI was performed every 3 to 6 months.  Among the enrolled patients, the technical success rate of one-lung ventilation was 92.2 % (59/64).  The visibility scores of tumors were improved significantly after one-lung ventilation compared to those before one-lung ventilation (p < 0.001).  Finally, 78.6 % (55/70) of the tumors achieved clinical success of one-lung ventilation to become clearly visible and underwent thermal ablation; 14 of the remaining 15 tumors achieved a satisfactory acoustic window after combination of artificial pleural effusion.  One lesion remained inconspicuous and partly affected by pulmonary gas.  The follow-up period was 8 months (3 to 30 months).  The technical efficacy rate was confirmed to be 100 % (75/75).  During the follow-up period, local tumor progression occurred in 2 patients (2/75, 2.7 %).  Major complications occurred in 2 patients (2/64, 3.1 %) receiving one-lung ventilation.  The authors concluded that one-lung ventilation is a promising non-invasive method for the thermal ablation of hepatic dome tumors due to its safety and  efficacy.  This modality could improve the acoustic window for over 70 % of hepatic dome tumors.

The authors stated that this study had several drawbacks.  First, it was a single-arm study without a control group for comparison.  Second, the sample size was not sufficiently large (n = 64).  Third, the follow-up period for evaluating the long-term therapeutic effect was relatively short (8 months).  These researchers stated that further research is needed to validate the clinical value of one-lung ventilation.

Cryoablation Combined with Radiotherapy for the Treatment of Hepatic Malignancy

Liu and colleagues (2020) stated that the survival of patients treated with monotherapy for hepatic malignancies is not ideal.  A comprehensive program of cryoablation combined with radiotherapy for the treatment of hepatic malignancies resulted in less trauma to the patients.  It may provide an option for the treatment of patients with advanced hepatic malignancies.  These investigators reported 5 cases of advanced-stage hepatic malignancies treated in their hospital from 2017 to 2018, including 3 cases of primary HCC and 2 cases of metastatic hepatic carcinoma.  Subjects first received cryoablation therapy on their liver lesions.  The procedure consisted of 2 freeze-thaw cycles, and for each session, the duration of freezing was 13 to 15 mins, and the natural re-warming period was 2 to 8 mins.  Depending on the tumor size, the appropriate cryoprobes were selected to achieve complete tumor ablation to the greatest extent possible.  After cryoablation surgery, intensity-modulated radiotherapy (IMRT) for liver lesions was carried out, and the radiotherapy regimen was 5,400 cGy/18f and 300 cGy/f.  None of the 5 patients had AEs above grade-II, and their quality of life (QOL) was significantly improved.  Among them, 4 patients were free of disease progression in the liver lesions under local control, and their survival was prolonged; 3 patients were still alive.  The authors concluded that their clinical practice demonstrated that cryoablation combined with IMRT could be implemented safely.  Moreover, these researchers stated that the definitive effectiveness for hepatic malignancies needs to be confirmed in prospective, larger studies.

Endoscopic Ultrasound-Guided Radiofrequency Ablation for the Treatment of Hepatocellular Carcinoma in Cirrhosis

de Nucci and colleagues (2020) noted that the percutaneous approach allows for safe and effective treatment of liver lesions; however, in case of subcapsular or left segments location, this approach appeared to be less effective or unsafe.  Endoscopic US-guided RFA (EUS-RFA) is a new technique used to treat pancreatic and neuroendocrine tumors in patients unfit for surgery.  These researchers reported on the case of a 70-year old man with cirrhosis with a large subcapsular HCC in II-III-IVb segments, in which surgery or percutaneous therapies were not feasible; the subject was treated with EUS-RFA.  The HCC was treated using an EUS-RFA system, which consists of a 19-G water-cooled monopolar RFA needle and a dedicated generator system.  After a multi-disciplinary discussion, the lesion was ablated in 2 different sessions, which resulted in destruction of about 70 % of neoplastic tissue.  A second step surgery was needed, but initially refused by the patient.  The authors concluded that EUS-RFA could be an effective way to treat left hepatic lesions not manageable with conventional percutaneous methods.  This case report did not highlight concerns regarding the safety of this approach; thus, this observation needs to be validated in a larger series of patients with cirrhosis who have lesions located in the left EUS-approachable segments.

The authors stated that besides documenting the technique’s advantages, this case also raised questions regarding EUS-RFA.  First, previous experience with the VIVA generator system in the treatment of liver lesions was very limited.  These investigators decided to set the generator at a power of 30 W after testing the ablation capacity of the system on bovine livers (unpublished data).  A second critical issue regards the assessment of necrosis while performing RFA.  An indirect sign of the development of necrosis in this case was represented by the appearance of echogenic bubbles within the lesion.  Because echogenic steam occurs when the tissue temperature increases to more than 100 °C, development of bubbles involving the whole lesion and its borders can be interpreted as achievement of the maximal thermal effect on the tissue.  The absence of vital tissue was confirmed in this patient by performing CH-EUS with Sonovue; however, these researchers observed a significant discrepancy between the presumptive complete necrosis of the lesion as assessed at CH-EUS and the persistence of vital tissue at contrast-enhanced CT scan performed 30 days later.   It has been reported that CH-EUS performed more than 24 hours after treatment has very low sensitivity (27.3 %) for identifying vital neoplastic tissue when compared to CT scan performed 1 month after the procedure.  This is probably due to the fact that steam bubbles that develop during treatment may obscure part of the lesion, making it very difficult to differentiate residual neoplastic tissue from reactive hyperemia around the nodule.  This effect is likely to be more evident in cases of very large lesions and for those located away from the EUS probe, such as in this case.  In general, contrast-enhanced EUS is per se less sensitive than contrast-enhanced CT for evaluating exact nodule extension.  Possible disagreement in enhancement patterns between sonography/EUS and CT/MRI contrast agents may explain such a discrepancy; however, this aspect has to be studied in the future to improve real-time assessment of efficacy of the RFA procedure after lesion ablation.

Histotripsy of the Liver

Histotripsy of the liver (HistoSonics, Inc.) is an image-guided non-invasive automated external beam therapy using acoustic energy to mechanically destroy tissue in the liver without incisions, ionizing radiation or heat.  Histotripsy is also defined as "a tissue ablation method that utilizes focused high amplitude ultrasound to generate a cavitation bubble cloud that mechanically fractionates tissue" (Alavi Tamaddoni et al., 2019). "The non-thermal mechanism of action of histotripsy allows precise ablation with conversion of tissue to a liquefied homogenate and real-time ultrasound monitoring of the bubble cloud confirms targeting and progression of treatment" (Roberts, 2014). Unlike other treatment methods, the histotripsy platform allows physicians to monitor the destruction of tissue under continuous real time visualization and control. 

Histotripsy has been evaluated in clinical trials using animal models, which have shown promise for future cancer treatment. Histotripsy has been investigated for a wide range of applications in preclinical studies, including the treatment of cancer, neurological diseases, and cardiovascular diseases (Xu et al, 2021). There is a U.S. clinical trial underway to evaluate the safety and technical efficacy of histotripsy in patients with primary and secondary liver tumors.

The HistoSonics System for Treatment of Primary and Metastatic Liver Tumors Using Histotripsy (#HOPE4LIVER US) (NCT04572633) trial is a single arm, non-randomized prospective trial. Following histotripsy treatment of liver tumor(s), subjects will undergo imaging less than or equal to 36 hours post-index procedure to determine technical success. Subjects will then be followed for 30 days. Data through the 30-day time point will be used for a Regulatory Submission to the FDA. Additionally, subjects will be followed for five (5) years post-index procedure, with evaluations at the 6-month and annual time points to estimate the efficacy and safety profile of the HistoSonics System (HistoSonics, 2021c).

In October 2021, the U.S. Food and Drug Administration (FDA) granted HistoSonics, Inc. Breakthrough Device Designation for its new histotripsy platform (HistoSonics, 2021b). The American Medical Association (AMA) issued a new Category III Current Procedural Terminology (CPT) code for histotripsy of the liver effective January 1, 2022. 

The histotripsy device was cleared by the FDA based on a de novo 510(k) in October 2023. The data submitted to the FDA consisted of outcomes in 44 patients, 18 of which had hepatocellular carcinoma (HCC) tumors and 26 had metastatic tumors to the liver from the colon, rectum, breast, and other primary origins. The manufacturer reported a technical success rate of 95.5% (indicating that the device can target and destroy liver tissue and un-resectable liver tumors). Regarding safety, 3 procedure related grade 3 or higher adverse events through 30 days post-histotripsy were observed across all 44 subjects treated, representing a complication rate of 6.8%. There are a lack of reliable data on clinical outcomes and durability of results; clinical trials of histotripsy are ongoing.

Qu et al (2020) stated that developing the ability to use tumor-directed therapies to trigger potentially therapeutic immune responses against cancer antigens remains a high priority for cancer immunotherapy.  These researchers hypothesized that histotripsy, a novel non-invasive, non-thermal ablation modality that employs US-generated acoustic cavitation to disrupt tissues, could engender adaptive immune responses to tumor antigens.  Immunocompetent C57BL/6 mice inoculated with flank melanoma or HCC were treated with histotripsy, thermal ablation, radiation therapy (RT), or cytotoxic T lymphocyte-associated protein-4 (CTLA-4) blockade checkpoint inhibition.  Lymphocyte responses were measured using flow cytometric and immunohistochemical analyses.  The impact of histotripsy on abscopal immune responses was assessed in mice bearing bilateral tumors, or unilateral tumors with pulmonary tumors established via tail vein injection.  Histotripsy ablation of subcutaneous murine melanoma tumors stimulated potent local intra-tumoral infiltration of innate and adaptive immune cell populations.  The magnitude of this immune-stimulation was stronger than that observed with tumor irradiation or thermal ablation.  Histotripsy also promoted abscopal immune responses at untreated tumor sites and inhibited growth of pulmonary metastases.  Histotripsy was capable of releasing tumor antigens with retained immunogenicity, and this immunostimulatory effect was associated with calreticulin translocation to the cellular membrane and local and systemic release of high mobility group box protein 1.  Histotripsy ablation potentiated the effectiveness of checkpoint inhibition immunotherapy in murine models of melanoma and HCC.  The authors concluded that these pre-clinical observations suggested that non-invasive histotripsy ablation could be used to stimulate tumor-specific immune responses capable of enhancing the impact of checkpoint inhibition immunotherapy.

Hendricks-Wenger et al (2021) noted that cancer is the 2nd leading cause of death globally despite major advancements in diagnosis and therapy over the past century.  One of the most debilitating aspects of cancer is the burden brought on by metastatic disease; thus, an ideal therapeutic protocol would address not only debulking larger primary tumors but also circulating tumor cells and distant metastases.  To address this need, the use of immune modulating therapies has become a pillar in the oncology armamentarium.  A therapeutic option that has recently emerged is the use of focal ablation therapies that can destroy a tumor via various physical or mechanical mechanisms and release a cellular lysate with the potential to stimulate an immune response.  Histotripsy is a non-invasive, non-ionizing, non-thermal, US-guided ablation technology that has shown promise over the last 10 years as a debulking therapy.  As histotripsy therapies have developed, the full picture of the accompanying immune response has showed a wide range of immunogenic mechanisms that include damage-associated molecular patterns (DAMPs) and anti-tumor mediator release, changes in local cellular immune populations, development of a systemic immune response, and therapeutic synergism with the inclusion of checkpoint inhibitor therapies.  These studies also suggested that there is an immune effect from histotripsy therapies across multiple murine tumor types that may be reproducible.  The authors concluded that overall, the effects of histotripsy on tumors demonstrated a positive effect on immunomodulation.  Moreover, these researchers stated that while these data are certainly exciting, the number of studies in this field were still quite limited and most were based on murine models with inconsistent tumor ablation quality.  Looking towards the future, there needs to be an effort to compare the various histotripsy treatments and doses, as well as other mechanical HIFU (mHIFU) methods, in order to better understand the relationship between the extent of ablation in stimulating an immune response.  Similarly, as these therapies begin to be employed in human trials, it will be important to translate these findings into actionable results relevant to human patients.  These investigators stated that further basic studies and pre-clinical animal trials are also still needed to develop missing mechanistic insight and more translationally relevant studies are needed to ensure these findings occur outside of the typical model organisms.  These researchers stated that despite these limitations, the benefits of histotripsy over other thermal ablation modalities in pre-clinical work suggested the potential of this focal tumor ablation therapy to induce a systemic anti-tumor immune response; thus, supporting the hypothesis that histotripsy has the potential to positively impact the clinical outcomes for cancer patients.

Vidal-Jove et al (2021) presented a case report that demonstrated an abscopal effect in the context of a safety and effectiveness clinical trial for histotripsy as an ablation technique in hepatic tumors.  The abscopal effect appeared in the form of reduction in the volume of non-treated tumor lesions in the same organ, as well as sustained reduction of the tumor marker, carcinoembryonic antigen (CEA) that extended weeks away of the procedure.  The authors concluded that histotripsy is a novel, non-invasive, non-thermal, and non-ionizing precise ablation technique for tissue destruction guided by US.  They discussed the feasibility of this technique compared with other focal therapies and its possibilities as immune system enhancer.

Xu et al (2021) noted that histotripsy is the 1st non-invasive, non-ionizing, and non-thermal ablation technology guided by real-time imaging.  By means of focused US delivered from outside the body, histotripsy mechanically destroys tissue via cavitation, rendering the target into acellular debris.  The material in the histotripsy ablation zone is absorbed by the body within 1 to 2 months, leaving a minimal remnant scar.  Histotripsy has also been shown to stimulate an immune response and induce abscopal effects in animal models, which may have positive implications for future cancer treatment.  Histotripsy has been examined for a wide range of applications in pre-clinical studies, including the treatment of cancer, neurological diseases, and cardiovascular diseases.  To-date, 3 human clinical trials have been conducted using histotripsy for the treatment of benign prostatic hyperplasia (BPH), liver cancer, and calcified valve stenosis.  The authors provided a comprehensive overview of histotripsy covering the origin, mechanism, bioeffects, parameters, instruments, and the latest results on pre-clinical and human studies.  These researchers stated that despite substantial technical, pre-clinical, and clinical progress to-date, a large amount of future work is needed for technical development, pre-clinical research, and human studies before histotripsy can become a widespread clinical treatment modality.

Vidal-Jove et al (2022) stated that current hepatic loco-regional therapies are limited in terms of effectiveness and toxicities.  Given promising pre-clinical results, a 1st in-human study was designed to examine the technical effectiveness and safety profile of histotripsy in patients with primary and secondary hepatic tumors.  These researchers carried out a multi-center phase-I clinical trial (The Theresa Study) in a single country with 8 weeks of planned follow-up; 8 of the 14 recruited patients were deemed eligible and enrolled in the study.  Hepatic histotripsy was carried out with a prototype system (HistoSonics, Inc., Ann Arbor, MI).  A total of 11 tumors were targeted in the 8 patients who all had unresectable end-stage multi-focal hepatic tumors: Colo-rectal liver metastases (CRLM) in 5 patients (7 tumors), breast cancer metastases in 1 (1 tumor), cholangiocarcinoma metastases in 1 (2 tumors), and HCC in 1 (1 tumor).  The primary endpoint was acute technical success, defined as creating a zone of tissue destruction per planned volume assessed by MRI 1 day post-procedure.  Safety (device-related AEs) through 2 months was a secondary endpoint.  The 8 patients had a median age of 60.4 years with an average targeted tumor diameter of 1.4 cm.  The primary endpoint was achieved in all procedures.  The secondary safety profile endpoint identified no device-related AEs.  A total of 2 patients experienced a continuous decline in tumor markers during the 8 weeks following the procedure.  The authors concluded that this 1st-in-human study showed that hepatic histotripsy effectively destroyed liver tissue in a predictable manner, correlating very well with the planned histotripsy volume, and exhibited a high safety profile without any device-related AEs.  These investigators stated that based on these findings, the need for more definitive clinical trials is needed.

Wade et al (2023) noted that a wide range of ablative and non-surgical therapies are available for treating small HCC in patients with very early or early-stage disease and preserved liver function.  In a systematic review and network meta-analysis, these investigators compared the effectiveness of all current ablative and non-surgical therapies for patients with small HCC (3 cm or less).  They searched 9 data-bases (March 2021), 2 trial registries (April 2021) and reference lists of relevant systematic reviews.  Eligible studies were RCTs of ablative and non-surgical therapies, versus any comparator, for small HCCs; RCTs were quality assessed using the Cochrane Risk of Bias 2 tool and mapped.  The comparative effectiveness of therapies was assessed using network meta-analysis.  A threshold analysis was used to identify which comparisons were sensitive to potential changes in the evidence.  Where comparisons based on RCT evidence were not robust or no RCTs were identified, a targeted systematic review of non-randomised, prospective comparative studies provided additional data for repeat network meta-analysis and threshold analysis.  The feasibility of undertaking economic modelling was examined.  A work-shop with patients and clinicians was held to discuss the findings and identify key priorities for future research.  A total of 37 RCTs (with over 3,700 relevant patients) were included in the review.  The majority were carried out in China or Japan, and most had a high risk of bias or some risk of bias concerns.  The results of the network meta-analysis were uncertain for most comparisons.  There was evidence that percutaneous ethanol injection (PEI) was inferior to RFA for OS (HR 1.45, 95 % CI: 1.16 to 1.82), PFS (HR 1.36, 95 % CI: 1.11 to 1.67), overall recurrence (relative risk 1.19, 95 % CI: 1.02 to 1.39) and local recurrence (relative risk 1.80, 95 % CI: 1.19 to 2.71).  PEI was also inferior to RFA for PFS (HR 1.63, 95 % CI: 1.05 to 2.51).  Threshold analysis showed that further evidence could plausibly change the result for some comparisons.  A total of 14 eligible non-randomised studies were identified (n of 2,316 or more); 12 had a high-risk of bias so were not included in updated network meta-analyses.  Additional non-randomised data, made available by a clinical advisor, were also included (n = 303).  There remained a high level of uncertainty in treatment rankings after the network meta-analyses were updated.  However, the updated analyses suggested that MWA and resection were superior to PEI and percutaneous acid injection for some outcomes.  These investigators stated that further research on stereotactic ablative RT was recommended at the work-shop, although it is only appropriate for certain patient subgroups, limiting opportunities for adequately powered trials.  The authors concluded that the available evidence base has limitations; the uptake of specific ablative therapies in the U.K. appeared to be based more on technological advancements and ease of use than strong evidence of clinical effectiveness; however, there is evidence that PEI and percutaneous acid injection are inferior to RFA, MWA, and resection.  The authors found no studies that compared electrochemotherapy, histotripsy, stereotactic ablative RT or wider RT techniques with other treatments.  Only 2 studies reported data on QOL or patient satisfaction.  These investigators discussed the findings with patients and clinical experts.  Stereotactic ablative RT was highlighted as a treatment that requires further research; however, it is only appropriate for certain subgroups of patients.  Feasibility studies could inform future clinical trials by examining issues such as whether patients are willing to take part in a trial or find the treatments acceptable.  Moreover, these researchers stated that many studies were small and of poor quality; and no comparative studies were found for some therapies.

Osada et al (2023) stated that mechanical HIFU (M-HIFU), which includes histotripsy, is a non-ionizing, non-thermal ablation technology that can be delivered by non-invasive methods.  Because acoustic cavitation is the primary mechanism of tissue disruption, histotripsy is distinct from the conventional HIFU techniques resulting in hyperthermia and thermal injury.  Phase-I human clinical trials have shown the initial safety and effectiveness of histotripsy in treating patients with malignant liver tumors.  In addition to tissue ablation, a promising benefit of M-HIFU has been stimulating a local and systemic anti-tumor immune response in pre-clinical models and potentially in the phase-I clinical trial.  Pre-clinical studies combining systemic immune therapies appeared promising; however, clinical studies of combinations have been complicated by systemic toxicities.  Consequently, combining M-HIFU with systemic immunotherapy has been demonstrated in pre-clinical models and may be tested in future clinical studies.  An additional alternative is to combine intra-tumoral M-HIFU and immunotherapy using microcatheter-placed devices to deliver both M-HIFU and immunotherapy intratumorally.  The promise of M-HIFU as a component of anti-cancer therapy is promising; however, as forms of HIFU are tested in pre-clinical and clinical studies, investigators should report not only the parameters of the energy delivered but also details of the pre-clinical models to enable analysis of the immune responses.  Finally, as clinical trials continue, clinical responses and immune analysis of patients undergoing M-HIFU including forms of histotripsy will provide opportunities to optimize clinical responses and to optimize application and scheduling of M-HIFU in the context of the multi-modality care of the cancer patient.

Iqbal et al (2024) noted that histotripsy is a non-invasive medical technique that uses HIFU to treat liver tumors.  The 2 main histotripsy methods are boiling histotripsy and cavitation cloud histotripsy.  Boiling histotripsy uses prolonged US pulses to create small boiling bubbles in the tissue, which results in the break-down of the tissue into smaller sub-cellular fragments.  Cavitation cloud histotripsy employs the ultrasonic cavitation effect to disintegrate target tissue into precisely defined liquefied lesions.  Both methods show similar treatment effectiveness; however, boiling histotripsy ensures treatment stability by producing a stable boiling bubble with each pulse.  The therapeutic effect is ascribed to mechanical damage at the sub-cellular level rather than thermal damage.  The authors concluded that histotripsy is a novel technique for medical care that offers a highly focused and minimally invasive method to treat a variety of illnesses, such as calcified aortic stenosis, BPH, and liver tumors.  The procedure is a promising option for patients and clinicians because it is non-surgical, disrupts tissue at the cellular level, and allows quick absorption.  Even though there are some possible drawbacks and issues, such as the inapplicability of gas-filled locations, the risk of thrombosis, and concerns regarding tumor cell release, further research showed that these difficulties are often out-weighted by their advantages.  These investigators stated that histotripsy has great potential to transform the way many diseases are treated, as well as to enhance overall prognosis and QOL as it develops and advances. 

Sandilos et al (2024) stated that histotripsy is a novel, US-based ablative technique that was recently approved by the FDA for hepatic targets.  It has several promising additional theoretical applications that need to be further examined.  Its basis as a non-thermal, cavitational technology presents a unique advantage over existing thermal ablation techniques in maximizing local effects while minimizing adjacent tissue destruction.  These investigators discussed the technical basis and available pre-clinical and clinical data regarding histotripsy.  This was a comprehensive review of the literature on histotripsy and the clinical landscape of existing ablative techniques using the PubMed database.  A technical summary of histotripsy's physics and cellular effect was described.  Moreover, data from recent clinical trials, including Hope4Liver, and future implications regarding its application in various benign and malignant conditions were discussed.  Pre-clinical data showed the effectiveness of histotripsy ablation in various organ systems with minimal tissue destruction when examined at the histologic level.  The 1st prospective clinical trial involving histotripsy in HCC and liver metastases, Hope4Liver, reported a primary effectiveness of 95.5 % with minimal complications (6.8 %).  This effectiveness was replicated in similar trials entailing the treatment of BPH.  The authors concluded that in addition to the non-invasive ability to ablate lesions in the liver, histotripsy offers additional therapeutic potential.  Early data suggested a potential complementary therapeutic effect when combining histotripsy with existing immunologic therapies because of the technology's theoretical ability to sensitize tumors to adaptive immunity.  Moreover, these researchers stated that as with most novel therapies, the effect of histotripsy on the oncologic therapeutic landscape remains uncertain.

Verma and Perera Molligoda Arachchige (2024) stated that tissue ablation techniques have long been used in clinical settings for the treatment of various malignant diseases; however, many of these techniques are invasive and can cause substantial adverse effects.  Histotripsy is a non-invasive, non-ionizing, non-thermal tissue ablation technique that has the potential to replace surgical interventions in various clinical settings.  Histotripsy works by delivering HIFU waves to target tissue.  These waves create cavitation bubbles within tissues that rapidly expand and collapse; thus, mechanically fractionating the tissue into acellular debris that is subsequently absorbed by the body's immune system.  Pre-clinical and clinical studies have reported the effectiveness of histotripsy in treating various diseases, including liver, pancreatic, renal, and prostate tumors.  Safety outcomes of histotripsy have been generally favorable, with minimal adverse effects reported.  Moreover, these investigators stated that further studies are needed to optimize the technique, determine its long-term effects and its potential applications in clinical practice.  The authors concluded that histotripsy holds the potential to revolutionize medical treatment with its non-invasive, tissue-selective capabilities if its current limitations are carefully addressed.

Xu et al (2024) noted that histotripsy is a relatively new therapeutic US technology to mechanically liquefy tissue into sub-cellular debris using high-amplitude focused US pulses.  Contrary to conventional HIFU thermal therapy, histotripsy has specific clinical advantages: the capacity for real-time monitoring using US imaging, diminished heat sink effects resulting in lesions with sharp margins, effective removal of the treated tissue, a tissue-selective feature to preserve crucial structures, and immune-stimulation.  The technology is being evaluated in small and large animal models for the treatment of cancer, thrombosis, hematomas, abscesses, and biofilms; enhancing tumor-specific immune response; as well as neurological applications.  Histotripsy has been recently approved by the FDA for the treatment of liver tumors, with clinical trials undertaken for BPH and renal tumors.  The authors concluded that the promising abscopal effect induced by histotripsy alone from pre-clinical studies and the THERESA Trial demonstrated the potential of using histotripsy to enhance immunotherapy to treat off-target tumors.  The immune-stimulation effect observed in the treatment of non-immunogenic cancers such as liver cancer is especially encouraging and is drawing many researchers to further study this topic.  It is expected that there will be a major push to initiate a clinical trial on histotripsy-enhanced immunotherapy in the near future, which will aid in accelerating the widespread use of histotripsy, if it is successful.

Worlikar et al (2024) stated that histotripsy is the 1st non-invasive, non-ionizing, and non-thermal ablation technique that mechanically fractionates target tissue into acellular homogenate via controlled acoustic cavitation.  Histotripsy has been examined for various pre-clinical applications requiring non-invasive tissue removal including cancer, brain surgery, blood clot and hematoma liquefaction, as well as correction of neonatal congenital heart defects.  These researchers noted that histotripsy has shown promising results for treating cancers in different anatomic locations in-vivo.  Pre-clinical studies have reported on the safety, feasibility, radiological and histological characterization of tumors, survival outcomes, immunomodulatory effects, and treatment outcomes with combination approaches in a spectrum of tumor models as well as in veterinary patients with naturally occurring tumors.  Ongoing human clinical trials have reported promising early results.  Histotripsy has recently been approved by the FDA to non-invasively treat liver tumors.  In addition to being used as a stand-alone therapy, the combination of histotripsy with other treatment modalities such as immunotherapy and chemotherapy is currently under investigation in various tumor models.  The authors hoped that the insights and challenges discussed in this review will help future in-vivo pre-clinical development of histotripsy, with the objective of clinical adoption.

Campbell and Makary (2024) noted that image-guided solid tumor ablation methods have significantly advanced in their capability to target primary and metastatic tumors.  These techniques involve non-invasive or percutaneous insertion of applicators to induce thermal, electrochemical, or mechanical stress on malignant tissue to cause tissue destruction and apoptosis of the tumor margins.  Ablation offers substantially lower risks compared to traditional methods.  Benefits include shorter recovery periods, reduced bleeding, and greater preservation of organ parenchyma compared to surgical intervention.  Due to the reduced morbidity and mortality, image-guided tumor ablation offers new opportunities for treatment in cancer patients who are not candidates for resection.  Presently, image-guided ablation techniques are used for the treatment of primary and metastatic tumors in various organs with both curative and palliative intent, including the liver, pancreas, kidneys, thyroid, parathyroid, prostate, lung, breast, bone, and soft tissue.  These investigators stated that histotripsy differs from thermoablation techniques that use electromagnetic radiation or US waves to carry out thermal stress to induce cell death; histotripsy induces cell death via mechanical stress.  Histotripsy creates targeted cavitations with large-amplitude US pulses to mechanically disintegrate tissue.  These cavitations are microbubbles formed from pressure waves of high-amplitude sound waves traveling through a fluid.  The pressure waves and cavitations generate sheer stress that mechanically break cells into sub-cellular components.  These researchers noted that there are several pre-clinical studies performed on tumors located in several organ systems: brain, liver, prostate cancer, renal cancer, breast cancer, pancreatic cancer, and musculoskeletal cancer.  In addition to showing the ability to target and ablate tumors effectively, histotripsy has shown the ability to trigger an immune response, resulting in a subsequent abscopal effect in animal tumor models.  While these are all potential applications, most of the trials on humans have focused on BPH and hepatic tumors.  There is currently an ongoing clinical trial to examine tumor ablation in the kidney.

Mendiratta-Lala et al (2024) stated that histotripsy is a non-thermal, non-ionizing, non-invasive, focused US technique that relies on cavitation for mechanical tissue breakdown at the focal point.  Pre-clinical data have shown its safety and technical success in the ablation of liver tumors.  These researchers examined the safety and technical success of histotripsy in destroying primary or metastatic liver tumors.  The parallel United States and European Union and England #HOPE4LIVER Trials were prospective, multi-center, single-arm studies.  Eligible patients were recruited at 14 sites in Europe and the U.S. from January 2021 to July 2022.  Up to 3 tumors smaller than 3 cm in size could be treated.  CT or MRI and clinic visits were carried out at 1 week or less before procedure, at index-procedure, 36 hours or less after procedure, and 30 days after procedure.  There were co-primary end-points of technical success of tumor treatment and absence of procedure-related major complications within 30 days, with performance objectives of greater than 70 % and less than 25 %, respectively.  A 2-sided 95 % Wilson score CI was derived for each end-point.  A total of 44 subjects (21 from the U.S., 23 from the E.U. or England; 22 women, 22 men; mean age of 64 years ± 12 [SD]) with 49 tumors were enrolled and treated.  A total of 18 (41 %) had HCC and 26 (59 %) had non-HCC liver metastases.  The maximum pre-treatment tumor diameter was 1.5 ± 0.6 cm and the maximum post-histotripsy treatment zone diameter was 3.6 ± 1.4 cm.  Technical success was observed in 42 of 44 treated tumors (95 %; 95 % CI: 84 % to 100 %) and procedure-related major complications were reported in 3 of 44 subjects (7 %; 95 % CI: 2 % to 18 %), both meeting the performance objective.  The authors concluded that the #HOPE4LIVER Trials met the co-primary end-point performance objectives for technical success and the absence of procedure-related major complications, supporting early clinical adoption.  Moreover, these investigators stated that larger studies with longer follow-up in typical candidates for local-regional treatment will provide further outcome data to aid in define the role of this emerging technology.

The authors stated that this study had several drawbacks.  First, the small sample size (n = 44 subjects with 49 tumors) and short-term post-procedure follow-up (30 days) were limitations related to the nature of the study design.  These researchers stated that larger patient populations are likely to be reported when patient enrollment expands beyond a clinical trial.  Second, the technical success objective, although literature-based, was decided on with the FDA, based on an achievable patient enrollment goal, and was not intended to identify a difference from existing therapies.  These investigators stated that long-term follow-up of the current trial participants is planned and is expected to be reported in the future.  Third, given the lack of validated treatment-response criteria, the 30-day effectiveness assessments were extrapolated from existing standards of treatment response despite the unique mechanism of cell destruction when using histotripsy.  These researchers stated that an improved understanding of imaging outcomes is likely to evolve in future studies.  Fourth, the total procedure time was difficult to compare with that reported for existing therapies because researchers had no previous experience with this or similar externally delivered therapies.  Fifth, the patient population was not typical of those who undergo ablative therapies because many had stage-IV metastatic disease.  These somewhat limited the comparison of histotripsy with reported outcomes of other well-established local-regional treatments.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Hepatocellular Carcinoma” (Version 3.2024) does not mention histotripsy / high-intensity focused ultrasound / HIFU as a management option.

Microwave Ablation for the Treatment of Hepatocellular Carcinoma and Liver Metastases

Han et al (2022) noted that there is a myriad of microwave ablation (MWA) systems used in clinical settings worldwide for the management of liver cancer that offer a variety of features and capabilities.  However, an analysis on which features, and capabilities would result in the most favorable safety and effectiveness results has never been performed due to a lack of head-to-head comparisons.  These researchers compared single-antenna and multiple-antenna MWA using RFA as a common comparator in the treatment of very-early, early HCC and 5 cm or less liver metastases.  This network meta-analysis was carried out according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement.  PubMed, Cochrane, and Web of Science databases were searched for comparative studies.  Complete ablation (CA) rate, local tumor progression-free (LTPF) rate, OS, and major complication rate were assessed.  Subgroup analyses were further performed based on synchronous or asynchronous MWA generators and tumor size (less than 2 cm or 2 cm or larger).  A total of 21 studies (3,424 patients), including 3 RCTs and 18 observational studies, met eligibility criteria.  For CA, LTPF and major complications, as compared to single-antenna MWA, multiple-antenna MWA had RRs of 1.051 (95 % CI: 0.987 to 1.138), 1.099 (95 % CI: 0.991 to 1.246), and 0.605 (95 % CI: 0.193 to 1.628), respectively.  For 1-year and 3-year OS, as compared to single-antenna MWA, multiple-antenna MWA had ORs of 0.9803 (95 % CI: 0.6772 to 1.449) and 1.046 (95 % CI: 0.615 to 1.851), respectively.  Subgroup analysis found synchronized multi-antenna MWA was associated with significantly better LTPF by 22 % (RR: 1.22, 95 % CI: 1.068 to 1.421), and 21.4 % (RR: 1.214, 95 % CI: 1.035 to 1.449) compared with single-antenna MWA, and asynchronous multiple-antenna MWA, respectively, with more evident differences in larger tumors (2 cm or larger).  The authors concluded that multi-antenna and single-antenna MWA showed similar effectiveness for local treatment of liver tumors, but synchronous multi-antenna MWA exhibited better LTPF compared to other MWA approaches, especially for larger liver tumors (2 cm or larger).  Moreover, these researchers stated that large-scale RCTs should be conducted in a systematic manner to compared MWA with current standard therapies.

The authors stated that this systematic review and network meta-analysis had several drawbacks.  First, observational studies were included in the analysis as only a small number of RCTs were available.  Second, due to the nature of thermal ablation, blinding of participants’ assigned intervention during the trial could not be achieved in RCTs.  In light of this limitation, the results may be biased because of the confounding or selection of participants in the included studies.  These concerns, however, were partly eased from 2 aspects.  From the aspect of the bias assessment in this study, most of the studies have low risk in the selection of the study groups, the comparability of the groups, and the ascertainment of the exposure and outcome of interest.  From the aspect of the study design of the included studies, most were well-balanced for baseline co-variates, especially for the tumor size, and some of the studies used matching to control for differences or reported regression analyses, showing the minimal impact of potential effect modifiers on treatment outcomes.  Third, multiple antennas were used only for some tumors in the multiple-antenna MWA group while, for the other tumors in this group, single antennas were used.  In the ablation procedure, the number of antennas usually depends on the tumor size.  For tumors larger than the cut-off size in diameter (usually 2 cm, sometimes 3 cm), overlapping ablations were carried out; for others, single-antenna MWA was performed.  Since no studies discussed the results separately in the purely multiple-antenna ablations, it was impossible to isolate the multiple-antenna results in the NMA.  However, a subgroup analysis was carried out according to tumor size and found an increased performance of multiple-antenna MWA over single-antenna MWA mainly in tumors 2 cm or larger.

In a systematic review and meta-analysis, Tang et al (2023) examined the effectiveness of MWA and RFA for the management of patients with colorectal liver metastases (CRLM).  PubMed, Web of Science, Embase, CNKI and the Cochrane Library were searched from inception to May 2023, and studies that reported outcomes with comparison between MWA and RFA in CRLM treatment were selected by inclusion and exclusion criteria.  In addition, the peri-operative and survival data were statistically summarized and analyzed by Review Manager 5.4.  A total of 5 studies (MWA = 316 patients; RFA = 332 patients) were evaluated.  The results of meta-analysis showed that LTP in MWA group was significantly lower than that in RFA group (p < 0.05).  The1-year and 2-year DFS of the MWA group was significantly better than that of the RFA group with HR of 1.77 (95 % CI: 1.04 to 3.02; p = 0.04) and 1.60 (95 % CI: 1.09 to 2.35; p = 0.02), respectively.  The authors concluded that the LTP, and 1-year, and 2-year DFS of MWA were superior to RFA. 

No-Touch Radiofrequency Ablation for the Treatment of Earl-Stage Hepatocellular Carcinoma

Zheng et al (2023) stated that no-touch RFA (NT-RFA) is an emerging ablation technique, and its safety and feasibility have been reported in a large number of papers.  However, in this meta-analysis, OS, local tumor progression (LTP)  and the incidence of complications were not statistically significant.  This is contrary to people's general perception which may be that as fewer studies were included, the follow-up time was short, and there was no unified operating standard for NT-RFA technology; thus, it was impossible to get meaningful results.  These researchers stated that more high-quality studies are needed to examine the prognosis of NT-RFA in early-stage HCC.

3D Contour Simulation for Microwave Ablation of Liver Lesions

Faridi e al (2020) stated that computational models are frequently employed during the design and characterization of MWA devices, and have been proposed for pre-treatment planning.  These researchers examined 3D transient temperature and ablation profiles predicted by MWA computational models with temperature profiles measured experimentally using MR thermometry in ex-vivo bovine liver.  They carried out MWA in ex-vivo tissue under MR guidance using a custom, 2.45 GHz water-cooled applicator.  MR thermometry data were acquired for 2 mins before heating, during 5 to 10 mins microwave exposures, and for 3 mins following heating.  Fiber-optic temperature sensors were used to validate the accuracy of MR temperature measurements.  A total of 13 ablation experiments were performed using 30 to 50 W applied power at the applicator input.  MWA computational models were implemented using the finite element method, and incorporated temperature-dependent changes in tissue physical properties.  Model-predicted ablation zone extents were compared against MRI-derived Arrhenius thermal damage maps using the Dice similarity coefficient (DSC).  Before heating, the observed standard deviation of MR temperature data was in the range of 0.3 to 0.7°C.  Mean absolute error between MR temperature measurements and fiber-optic temperature probes during heating was in the range of 0.5 to 2.8°C.  The mean DSC between model-predicted ablation zones and MRI-derived Arrhenius thermal damage maps for 13 experimental set-ups was 0.95.  When comparing simulated and experimentally (i.e., using MRI) measured temperatures, the mean absolute error (MAE %) relative to maximum temperature change was in the range 5 % to 8.5 %.  The authors developed a system for characterizing 3D transient temperature and ablation profiles with MR thermometry during MWA in ex-vivo liver tissue, and used the system for experimental validation of MWA computational models.  These researchers stated that these results reported on the validity of transient temperature and ablation profiles predicted by the state-of-art computational models of MWA and paved the way for further development and investigation of models for ultimate application in pre-treatment planning of MWA ablation procedures.

The authors stated that this study had several drawbacks.  First, during MWA, the center of ablation region in the proximity of applicator lost water first and the water was driven outwards, evaporated and may re-condense in cooler regions away from the applicator.  This effect was not incorporated in the 3D computational model these investigators used for the assessment.  Second, changes in tissue physical properties at elevated temperatures were modeled as functions of temperature alone, based on the currently available models in the literature.  However, it was plausible that tissue properties may also be a function of rate of heating, in addition to temperature.  The impact of rate of heating and tissue water transport may be of most significance in proximity to the applicator, where the highest temperatures were observed; therefore,  and could have contributed to the discrepancy between model and experiment in these regions.  However, not accounting for these changes was not anticipated to have a significant impact on the extent of the ablation zone, which is governed by more temperatures at distances approximately 10 to 15 mm from the applicator.  Third,, the computational models did not account for tissue shrinkage,

In a systematic review, van Erp et al (2023) examined the available evidence on existing computational models for RFA and MWA planning of liver lesions and compared their accuracy.  These investigators carried out a literature search in the Medline and Web of Science data-bases.  Characteristics of the computational model and validation method of the included studies were retrieved.  The literature search identified 780 studies, of which 35 were included.  A total of 19 studies focused on simulating RFA zones, and 16 focused on MWA zones.  Out of the 16 studies simulating MWA, only 2 used in-vivo experiments to validate their simulations.  Out of the 19 studies simulating RFA, 10 used in-vivo validation.  Dice similarity coefficients describing the overlap between in-vivo experiments and simulated RFA zones varied between 0.418 and 0.728, with mean surface deviations varying between 1.1 mm and 8.67 mm.  The authors concluded that computational models to simulate ablation zones of MWA and RFA revealed considerable heterogeneity in model type and validation methods.  These researchers stated that it is currently unclear which model is most accurate and best suitable for use in clinical practice.  However, these researchers noted that several studies have reported a good correlation between simulated ablation zones and in-vivo ablations; they stated that further investigations on patient-specific parameters are needed to develop more accurate models that could be used for individualized treatment planning.

Heshmat et al (2024) noted that MWA of liver tumors presents challenges like under- and over-ablation, potentially resulting in inadequate tumor destruction and damage to healthy tissue.  These researchers developed personalized 3D models to simulate MWA for liver tumors, incorporating patient-specific characteristics.  The primary objective was to validate the predicted ablation zones compared to clinical outcomes, offering insights into MWA before therapy to facilitate accurate treatment planning.  Contrast-enhanced CT images from 3 patients were used to create 3D models.  The simulations used coupled electromagnetic wave propagation and bioheat transfer to estimate the temperature distribution, predicting tumor destruction and ablation margins.  The findings indicated that prolonged ablation did not significantly improve tumor destruction once an adequate margin was achieved, although it increased tissue damage.  There was a substantial overlap between the clinical ablation zones and the predicted ablation zones.  For patient 1, the Dice score was 0.73, indicating high accuracy, with a sensitivity of 0.72 and a specificity of 0.76.  For patient 2, the Dice score was 0.86, with a sensitivity of 0.79 and a specificity of 0.96.  For patient 3, the Dice score was 0.8, with a sensitivity of 0.85 and a specificity of 0.74.  Patient-specific 3D models showed potential in accurately predicting ablation zones and optimizing MWA treatment strategies.  The authors concluded that the findings of this review highlighted the significant potential of employing patient-specific 3D models in improving the precision and effectiveness of MWA treatments for liver tumors.  The results showed that 3D models could accurately predict ablation zones, align closely with clinical outcomes, and have higher accuracy than vendor prediction models; thus, they have the potential to improve treatment effectiveness.  By integrating detailed patient characteristics and leveraging computational simulations, these models allowed for more targeted ablation strategies, reducing the risk of recurrence and unnecessary damage to surrounding healthy tissues.  Moreover, these investigators stated that further investigations are needed, especially in refining these models to address the uncertainties surrounding the optimal ablation times, input power, and antenna placement management.  Lastly, it provided patient-centered MWA therapies, enhancing outcomes, and offering a higher standard of patient care.

These researchers stated that the small cohort was specifically selected based on the following criteria: all patients were treated using a single MWA antenna insertion without displacement and with consistent MWA device settings throughout their therapy.  These conditions were necessary to maintain controlled variables for accurately validating the predictive capabilities of 3D models against clinical outcomes and comparing these with the vendor prediction model.  The strict criteria were necessary for this initial validation study; however, the design of future studies must include the flexibility to predict the ablation in the diverse configurations of the range of patient characteristics observed clinically.  Furthermore, the study was carried out using a single vendor MWA device; future studies are needed to examine how these results predict the outcomes from other systems.  These investigators stated that future studies should also include evaluations of the changing physiological parameters, and expand the study to include more patients; thereby, enhancing the robustness and clinical relevance of the 3D modeling approach.

Dietrich et al (2024) stated that interventional MRI could provide a comprehensive setting for MWA of tumors with real-time monitoring of the energy delivery using MRI-based temperature mapping.  These researchers quantified the accuracy of 3D real-time MRI temperature mapping during microwave heating in-vitro by comparing MRI thermometry data to reference data measured by fiber-optical thermometry.  A total of 9 phantom experiments were examined in agar-based gel phantoms using an in-room MR-conditional microwave system and MRI thermometry.  MRI measurements were carried out for 700 s (25 slices; temporal resolution 2 s).  The temperature was monitored with 2 fiber-optical temperature sensors approximately 5 mm and 10 mm distant from the microwave antenna.  Temperature curves of the sensors were compared to MRI temperature data of single-voxel regions of interest (ROIs) at the sensor tips; the accuracy of MRI thermometry was assessed as the root-mean-squared (RMS)-averaged temperature difference.  A total of 18 neighboring voxels around the original ROI were also examined and the voxel with the smallest temperature difference was additionally selected for further evaluation.  The maximum temperature changes measured by the fiber-optical sensors ranged from 7.3 K to 50.7 K.  The median RMS-averaged temperature differences in the originally selected voxels ranged from 1.4 K to 3.4 K.  When evaluating the minimum-difference voxel from the neighborhood, the temperature differences ranged from 0.5 K to 0.9 K.  The microwave antenna and the MRI-conditional in-room microwave generator did not induce relevant RF artifacts.  The authors concluded that accurate 3D real-time MRI temperature mapping during microwave heating with very low RMS-averaged temperature errors below 1 K was feasible in gel phantoms.  Moreover, these researchers stated that further investigations of the accuracy and robustness of MRI-based temperature mapping in-vivo (e.g., in large-animal studies) are needed.

The authors stated that this study had several drawbacks.  First, all measurements of this study were conducted in-vitro in 2 kinds of gel phantoms.  While this provided improved reproducibility due to the high homogeneity of the phantoms, there were also several effects that were only present in-vivo and whose influence on the accuracy of MRI thermometry could therefore not be assessed in this setting.  In particular, MRI-based temperature measurements in-vivo are influenced by tissue heterogeneity, motion, macroscopic blood flow, perfusion, as well as other sources of physiological noise, which must be expected to reduce the accuracy of the measurements.  Therefore, measurements in phantoms could only provide a best-case estimation of temperature accuracies, whereas accuracies in-vivo must be expected to be worse.  Second, the 2 gel phantoms (water and saline-based) exhibited substantially different heating behavior with the water-based phantom showing much less effective heating by the available microwave system than the saline-based one.  As a consequence of the much more effective heating, the saline-based phantom showed some effects due to over-heating (i.e., gel vaporization close to the antenna) manifesting as noisy sensor data (at low over-heating as in experiments #1 and #2) or as atypical and invalid MRI thermometry data (as in the discarded experiment #4).  Third, this study was based on only 9 heating experiments (after the exclusion of 1 experiment with the over-heated gel) carried out at a field strength of 1.5 T.  However, the total number of evaluated data points was much higher since each experiment was carried out over 700 s with a temporal resolution of 2 s, providing 350 data points for each sensor, i.e., 6,300 data points with evaluable temperature data overall measurements.  Different results should be expected at 3T because of potentially different RF noise interactions between the microwave generator and the MRI system, a different MRI protocol (with, e.g., modified optimal echo time and receiver band-width), and potentially larger susceptibility artifacts around the microwave antenna.  Fourth, the spatial resolution of the echo-planar imaging (EPI) acquisition was relatively low (2.2 × 2.2 × 3.0 mm³).  These voxels were considerably larger than the sensitive volume of the fiber-optical sensors (with a sensitive area diameter of 300 µm); thus, no perfect agreement between sensor data and temperatures in single voxels could be expected.  However, the spatial resolution of the EPI protocol was limited by the required field of view, a feasible matrix size of 128 × 128, and signal-to-noise ratio considerations.  Fifth, there may be some influences of the fiber-optical sensors themselves on the accuracy of the MRI thermometry data, potentially worsening the determined accuracy values.  The measurement accuracy of the reference sensors could also slightly worsen the measured results.  However, since reference data were needed for this study, these effects could not be avoided and it should be noted that the actual accuracies may be even better than the ones determined in these experiments.

Percutaneous Microwave Ablation Guided by Contrast-Enhanced and 2D Ultrasound for the Treatment of Hepatic Alveolar Echinococcosis

Huang et al (2024) stated that US-guided MWA has become a popular method for the treatment of malignant liver tumors; however, few studies have examined its use in the treatment of hepato-alveolar echinococcosis (HAE).  In a retrospective, single-center study, these researchers examined the safety and effectiveness of contrast-enhanced (CE) US combined with two-dimensional (2D) US-guided MWA for the treatment of HAE in difficult/dangerous locations.  Data from 81 patients, who were diagnosed with hepatic alveolar hydatid disease in difficult/dangerous locations between January 2018 and January 2023, and underwent CE-US combined with 2D US-guided MWA, were analyzed.  After undergoing MWA, patients were followed-up to examine if the lesions recurred and to assess the therapeutic effect of MWA.  Pre-operatively, individualized strategies were designed for lesions in different locations, and different auxiliary ablation technologies were used for CE-US combined with 2D US-guided MWA to achieve complete inactivation of lesions in difficult/dangerous locations.  MWA was carried out on 89 HAE lesions in 81 patients.  The median diameter of the lesions was 2.86 cm (inter-quartile range [IQR] 2.36 to 3.49 cm).  The complete ablation rate after surgery was 100 %, with a recurrence rate of 11.11 %, and median follow-up of 24 months (IQR 12 to 48 months).  The incidence of minor complications was 14.81 %; no serious complications or deaths occurred.  Compared with before surgery, total bilirubin (TB), direct bilirubin (DB), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels increased (p < 0.001), albumin platelets and activated partial thromboplastin time decreased (p < 0.05), with no statistical difference in prothrombin time (p > 0.05).  The authors concluded that MWA may be a safe and effective method for treating HAE in difficult/dangerous locations, and may represent a new and alternative option for this patient population.

The authors stated that this trial had several drawbacks.  First, this was a retrospective study without a control group; however, these investigators compared these findings with those of other researchers.  Second, all lesions in this trial were less than 5 cm in diameter, and there was a lack of data supporting ablation in patients with lesions of greater than 5 cm.  Third, this was a single-center study with insufficient sample size and a large selection bias.

Percutaneous Thermal Segmentectomy for the Treatment of Liver Malignancies

Lucatelli et al (2024) noted that percutaneous thermal segmentectomy is a single-step combination of MWA, conducted during arterial occlusion obtained with a balloon micro-catheter, followed in the same session by balloon-occluded TACE.  In a retrospective, multi-center study, these investigators reported the mid-term oncological performance of this technique for liver malignancies of greater than 3.0 cm and identified risk factors for the loss of sustained complete response.  Oncological results were evaluated with CT or MRI according to m-RECIST (HCC) and RECISTv1.1 (metastasis/intra-hepatic cholangiocarcinoma, iCC) at 1-month, 3-6-month, and then at regular-6-month intervals.  To identify predictive variables associated with not achieving or losing complete response 2 mixed-effects multi-variable logistic regression models were constructed.  A total of 63 patients (40/23, male/female) with primary liver malignancies (HCC = 49; iCC = 4) and metastasis (n = 10) were treated.  Median diameter of target lesion was 4.5 cm (range of 3.0 to 7.0).  The median follow-up time was 9.2 months.  At 1-month follow-up, 79.4 % of patients presented with a complete response and the remaining 20.6 % were partial responders.  At the 3-6-month follow-up, reached by 59 of the initial 63 patients, 83.3 % showed a sustained complete response, while 10.2 % had a partial response and 8.5 % a local recurrence.  At the last follow-up, 69.8 % of the lesions showed a complete response.  The initial diameter of the target lesion of 5.0 cm or greater was the only independent variable associated with the risk of failure in maintaining a complete response at 6 months (OR = 8.58, 95 % CI: 1.38 to 53.43; p = 0.02).  The authors concluded that percutaneous thermal segmentectomy is a globally available alternative intervention that showed promising mid-term follow-up results for lesions greater than 3 cm, with its best performance between 3 and 5 cm, suggesting its potential role as an alternative to the oncological standard of care (SOC).

The authors stated that this study had several drawbacks; the main one being the absence of a control group.  Moreover, the retrospective and multi-centric study design of the study limited the ability to remove potential selection confounders and introduced potential confounders from the different strategies and management approaches adopted in the various centers.  Furthermore, this trial had a limited sample size (n = 63) and relatively short median follow-up time (9.2 months).  All these limitations were related to the novelty of this technique compared to other standards of practice.  These researchers stated that a longer enrollment and follow-up are needed to confirm these preliminary findings, which laid the foundation for a direct comparison with radio-embolization and surgery for tumors between 3 and 5 cm.

Stereotactic Percutaneous Electrochemotherapy for the Treatment Modality of Primary and Secondary Liver Malignancies

In a retrospective, single-center study, Luerken et al (2024) reported on the first results of safety, effectiveness, and outcome of CT-navigated stereotactic percutaneous electrochemotherapy (SpECT) in patients with primary and secondary liver malignancies.  This trial included 23 consecutive lesions in 22 patients who underwent SpECT for primary and secondary malignant liver lesions with locally curative intention.  The endpoints were primary technique effectiveness (PTE), LTP, TTP, as well as occurrence of AEs.  The mean maximum diameter of the treated lesions was 42 mm (range of 16 to 72).  Eight lesions were HCC (34.8 %), 5 lesions were colorectal liver metastases (21.7 %), 3 lesions were cholangiocellular carcinoma (13.0 %), and the other 7 lesions were liver metastases from different primary cancers (30.4 %).  PTE was achieved for 22 lesions (95.7 %).  The mean follow-up time was 15 months (0 to 39); and no LTP was observed.  In 6 patients (27.3 %), hepatic tumor progression was observed during follow-up with a mean TTP of 3.8 months (2 to 8).  In 10 procedures (43.5 %), minor complications (1 CIRSE Grade-2) and side effects occurred, but no major complications were observed.  The authors concluded that SpECT appeared to be a safe and effective new local treatment modality for primary and secondary liver malignancies.  These researchers stated that SpECT may have a critical impact on clinical management, especially for tumor lesions that are not amenable to traditional thermos-ablative procedures due to their size and/or challenging location.  The promising impact on outcome in terms of local tumor control may further lead to the establishment of SpECT as an integral part of the minimally invasive armamentarium for the treatment of primary and secondary liver cancer.

The authors stated that this trial had several drawbacks.  First, as a retrospective, single-center study, the findings may not be fully generalizable to other clinical environments that employ different equipment, have varying levels of operator experience, or involve diverse patient populations.  Second, the small sample size (n = 22 patients) and relatively short follow-up period (mean follow-up of 15 months) may hinder the robustness of these findings.  Third, the absence of a control group complicated the interpretation of treatment efficacy.  Moreover, the substantial heterogeneity within the study cohort, which includes patients with different tumor entities, varying histological types, and a range of prior oncological treatments (e.g., liver surgery, systemic treatment, etc.), may significantly limit the ability to detect meaningful variations in treatment outcomes.  Fourth, while an outcome analysis focusing on OS would have been desirable as a primary endpoint, the afore-mentioned limitations may substantially bias this survival analysis, which is only relevant to the scientific community in strictly defined clinical scenarios.  This was exemplified by the CLOCC Trial, which showed a significant OS benefit of combining local treatment (i.e., RFA with or without surgical resection) plus systemic therapy compared to systemic treatment alone in patients with unresectable colorectal liver metastases without extra-hepatic disease.

Furthermore, National Comprehensive Cancer Network’s clinical practice guideline on “Hepatocellular Carcinoma” (Version 3.2024) does not mention stereotactic percutaneous electrochemotherapy as a management option.

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References