Abstract
Background: Thermal ablative techniques have gained increasing popularity as safe and effective options for patients with unresectable solid malignancies. Microwave ablation has emerged as a relatively new technique with the promise of larger and faster ablation areas without some of the limitations of radiofrequency thermal ablation. Herein, we report our preliminary results on the feasibility and efficacy of thermal ablation for hepatocellular carcinoma (HCC) with a new 2.45-MHz microwave generator. Patients and Methods: Under ultrasound guidance 194 HCCs in 144 patients were treated through a percutaneous approach. The median diameter of lesions was 2.7 cm (range=2.0-11.0 cm); 68 lesions had a diameter greater than 30 mm. We used a microwave generator (AMICA-GEM, Apparatus for MICrowave Ablation) connected to a 14- or 16-gauge coaxial antenna endowed with a miniaturized sleeve choke to reduce back heating effects and increase the sphericity of the ablated area. Contrast-enhanced computed tomography scan was carried out one month after treatment, and then every three months to assess efficacy. Results: Complete ablation was achieved in 94.3% of the lesions after a mean of 1.03 percutaneous sessions. For small HCCs (diameter <3 cm) complete necrosis was obtained in 100%. Local tumor progressions were found in 10 treated lesions (5.1%) a median of 19.5 months after ablation. Minor complications occurred in 5.1% procedures. No deaths, or other major complications occurred. Conclusion: In our experience, the new device for microwave ablation proved to provide an effective and safe percutaneous ablative method, capable of producing large areas of necrosis.
Hepatocellular carcinoma (HCC) is the fifth most common malignancy and the third leading cause of cancer death worldwide (1). Although hepatic resection is the preferred treatment option for patients with well-compensated cirrhosis with early-stage HCC, other non-surgical treatments, such as local ablation therapies, have gained a growing popularity as alternative therapies due to their minimal invasiveness, efficacy, easy repeatability, and cost-effectiveness (2). Radiofrequency ablation (RFA), the most common technique worldwide, was developed in Western countries at the beginning of the 1990s (3, 4). Microwave ablation (MWA), another ablative technique developed mainly in Oriental countries, only recently gained popularity in Western countries (5, 6).
Although both treatments induce thermal ablation of tumor tissues, the mechanisms of heat generation are different due to the different source of energy employed and its different propagation in tissues. MWA technology has several theoretical advantages compared with RFA: first of all, it achieves a greater penetration of energy into tissues, resulting in less susceptibility to convective heat loss from hepatic blood flow, and low sensitivity to local variation in tissue physical properties, such as impedance (7, 8). For that reason, MWA technology was expected to obtain larger volumes and faster area of thermal ablation with respect to RFA (9). However, the ablation zones obtained by first-generation MWA devices were frequently smaller and had a less rounded shape than those obtained by RFA apparatus. The improvement of microwave technology has led to the development of more powerful generators, able to obtain volumes of necrosis greater than previously, but with ellipsoidal areas of necrosis, due to uncontrolled microwave power reflection along the track of electrode insertion. This phenomenon, also known as the ‘comet’ effect, has made the MWA method not entirely suitable for the treatment of substantially spherical lesions, such as the nodules of HCC (6, 10).
We used a new microwave generator (AMICA-GEM, Apparatus for MICrowave Ablation) connected to a 14- or 16-gauge (G) coaxial antenna working at 2,450 MHz and endowed with a miniaturized sleeve choke in order to reduce back-heating effects and increase the sphericity of the area of necrosis.
In the current study we report on the short-term results of our mono-institutional experience using this new percutaneous device for the thermal ablation of HCC.
Patients and Methods
Patients' characteristics. In our retrospective study, between June 2009 and September 2011, percutaneous MWA was performed for 194 HCCs in 144 patients affected by hepatic cirrhosis in our institution. Inclusion criteria were as follows: age >18 years; Eastern Cooperative Oncology Group performance status 0 or 1; histological or radiological diagnosis of HCC; disease limited to the liver, with no more than three lesions; appropriate visualization of lesions on ultrasounds (US); lesions far from intestinal loops, gallbladder or main bile ducts; unsuitable for or refused surgical resection; liver function status at Child-Pugh score ≤B8; absence of major portal vein thrombosis; platelet count greater than 50,000/mm3; prothrombin time greater than 60%; total bilirubin concentration <3 mg/dl. The study population consisted of 144 patients, 94 men (65%) and 50 women (35%), with a median age of 75 years (range=60-87 years). The etiology of the underlying liver disease was hepatitis C (HCV) infection in 106 patients, hepatitis B (HBV) in six, alcoholic-hepatitis in 10, HCV and HBV co-infection in eight, HCV infection and alcohol abuse in 10 and cryptogenic chronic liver disease in four patients. Among these 194 HCCs, 35% were confirmed by histopatological analysis on biopsy samples obtained with an 18-G cutting needle and the remaining 65% were considered HCC on the basis of clinical and radiological criteria of the American Association for the Study of Liver Disease (11). The median diameter of these 194 HCCs was 2.7 cm (range=2.0-11 cm). Lesions were defined as small, intermediate or large depending on the main diameter, corresponding to <3 cm, ≥3 cm and <5 cm and ≥5 cm respectively. Patients' and tumors' characteristics are reported in Table I.
Before treatment, all patients underwent routine laboratory tests and an abdomen ultrasound to evaluate the location of the lesion and its relationship to closer vessels, gallbladder or bowel loops. A written informed consent for the ablation procedure approved by the Ethics Committee of the Institution was obtained from each patient before the treatment.
Treatment modality. MWA was performed using a dedicated solid-state programmable microwave 2.45-MHz generator (AMICA-GEN; HS Hospital Service SpA, Aprilia, Italy) delivering energy of 40-100 W through a 14- or 16-G internally cooled, coaxial antenna (AMICA-PROBE; HS Hospital Service SpA), featuring a miniaturized quarter-wave impedance transformer (mini-choke) for reflected wave confinement. An automatic peristaltic pump was used for applicator cooling to avoid probe overheating (Figure 1).
MWA was performed with US guidance through a percutaneous approach; the choice at using a 14-G or 16-G antenna was made according to the size and site of the lesion, taking into account the different powers that can be used with the two types of antennas (up to 80 W for 14-G antenna; up to 40 W for 16-G antenna). A 14-G antenna was used for the treatment of 134 lesions (69%), while a 16-G one was used for 60 lesions (31%).
The approach was subcostal in 47% of cases, intercostal in 52% of cases, while a combined approach was followed in 1% of the procedures. The duration of the ablation procedures, ranging from 3 to 16 min, was established according to the size of the lesions (relying on ex vivo data, supplied by the manufacturer, on bovine liver).
Furthermore, the size and the shape of the hyperechoic zone caused by gas microbubbles appearing in the ablation zone the during MWA procedure was monitored by US to assess the completeness of therapy. Treatment was stopped when the entire target was completely hyperechoic. The hyperhecoic zone did not always perfectly reproduce the shape of the lesion, neither was it perfectly confined to the lesion. In some instances, for example the use of high powers, the hyperechoic spots also extended along the needle track producing a tent-shaped ablation area with the vertex at the point of the needle insertion into the liver.
Patients were treated under unconscious sedation with intravenous administration of fentanyl and propofol, in spontaneous breathing with oxygen mask support.
Treatment was defined as the whole number of sessions or procedures required to achieve complete ablation of the lesion; specifically, one treatment was defined as a maximum of four procedures in an interval time of three months.
Assessment of treatment response. An abdominal contrast-enhanced computed tomographic scan was performed for all patients 30±10 days after the treatment, then every three months for the first year of follow-up, and then every six months during the next follow-up period. Complete ablation was defined as complete absence of contrast enhancement, with homogeneous hypodensity in the ablation zone; the opposite was defined as incomplete ablation.
Patients in whom complete ablation was achieved after the treatment underwent follow-up, while patients in whom complete ablation was not achieved were scheduled for other therapies, such as a new session of percutaneous MWA, surgery, laparoscopic thermal ablation, percutaneous ethanol injection (PEI), transarterial chemoembolization (TACE), medical therapies, or a combination of two or more of the above treatments, depending on the features of each single clinical case.
The tumor re-growth in the ablated zone or in the adjacent territory was defined as local tumor progression (LTP), while the appearance of new lesions within the liver parenchyma or at another site was defined as distant tumor progression (DTP) according to standards of the terminology (12). Patients with new lesions or LTP were planned for further treatment (such as MWA, PEI, TACE or others), depending on the individual case features.
To estimate the amplitude of the ablation zone obtained by MWA for each lesion, we calculated the difference between the volume of the ablation zone and the baseline volume of the treated lesion: this difference was defined as Δ volume. Using the equation for the volume of an ellipsoid, multiplying the largest three diameters on sagittal and axial planes obtained by enhanced abdominal CT scans (performed immediately before and one month after MWA), the volumes before and after MWA were calculated (13).
Statistical analysis. Descriptive statistics were calculated for all variables reporting mean and standard deviation for quantitative variables with Gaussian distribution, median and range for ordinal or quantitative variables with Gaussian distribution, and frequency and percentage for qualitative categorical or variables.
Results
The median follow-up period of the study population was nine months (range 1-31 months). Complete ablation was achieved in 183 lesions (94.3%), after a mean of 1.03 (SD=0.17) percutaneous MWA sessions (Figure 2). The rate of complete ablation was mainly related to the lesion size. For small HCCs, complete ablation was obtained in 100%, while the rate of complete ablation was 90% and 69% for the intermediate and large lesions, respectively. Out of the 11 tumors (5.6%) for which complete ablation was not obtained (Figure 3), six were subsequently treated with locoregional therapies (four with TACE and two with TACE combined with MWA), obtaining complete response. One tumor with a 5.7 cm diameter, located in the fifth segment not more far than 1 cm from the gallbladder wall, was surgically removed; histopathological examination demonstrated nearly complete necrosis, with an area of less than 1 cm2 of residual pathological tissue, as shown in the preoperative CT scan. With reference to the remaining four lesions, each belonging to a single patient, a multifocal progression of disease was detected and treated with sorafenib in three patients, while the other patient was treated only with supportive care, owing to a rapid decline of liver function. During the follow-up period, LTP was found in 10 treated lesions (two small, six intermediate and two large HCCs) belonging to eight patients, a median of 19.5 months (range=12-27 months) after MWA treatment. LTPs were subsequently treated with MWA in four cases and with TACE in the other six. DTPs with lesions within the liver parenchyma were found in 40 out of 144 patients (27.7%), at a median of 6 months (range=4-23 months) after MWA treatment. Among these patients, six had concomitant extra-hepatic disease progression, with lung metastases in two patients and bone metastases in four.
For small lesions, the median Δ volume obtained with a 14-G antenna was 11.2 cm3, representing an increase of almost 100% of the volume of a 3-cm diameter lesion, while for intermediate and large lesions, the increase was less extensive. In the intermediate and large HCCs in which complete ablation was not reached, the Δ volume was a negative value (Table II).
Our study confirmed that MWA is a very fast procedure. As shown in Table III, the time of energy application differed according to the diameter of nodules. A mean time of only 6.3 minutes was sufficient to obtain an adequate ablation area for small HCCs, while for intermediate and large HCCs, the mean duration of the ablation was 10.1 min and 13.7 min, respectively.
As already explained, the major limitation of first-generation microwave technology was represented by the tendency to form an elliptical-shape area of necrosis. To assess how the ablated area was similar to a spherical shape, for each lesion, we calculated the greater and the smaller diameter ratio (with spherical lesion having a ratio equal to 1). The results obtained, reported in Table II, show that the new device, limiting the backscattering of the reflected microwaves, was able to form ablation areas of almost spherical shape, independently of the dimension of the treated tumor.
Complications. Some complications occurred in our series, have already been reported in a recent study by Livraghi et al. who collected the results of a multicenter study (14). No ablation-related death nor major complication (defined as any event that leads to substantial morbidity and disability, increasing the level of care, or results in hospital admission or substantially lengthened hospital stay) occured. Minor complications occurred in 10 out of 194 sessions (5.1%). These cases included: a small asymptomatic pleural effusion not requiring drainage (n=4), a cutaneous burn occurring in the treatment of a partially esophytic subcapsular lesion (n=2). Mechanical damage to the probe tip (composed of a ceramic sleeve surrounding the antenna coaxial emitter, in turn loaded with a sharp stainless steel point) was observed in four procedures, either during probe insertion into the target or when withdrawing the probe after ablation (Figure 4). All probe tip fragility issues refer to an early version of the MWA applicator, featuring an aluminium oxide sleeve in its distal emitting portion. These issues seemed to have been completely overcome in a more recent model of the same probe, featuring zirconium instead of aluminium oxide. Nevertheless, tip detachment did not cause symptoms or long-term local or distant complications.
Discussion
Local ablation is considered the first line treatment option for patients with early-stage disease, not suitable for surgical therapy (2). For many years, PEI has been the main technique for percutaneous treatment of HCC. Thermal ablative techniques were then developed, including RFA, MWA, laser ablation and cryoablation. RFA, with respect to other methods, showed a higher anticancer effect than PEI in patients with HCC, leading to a better control of the disease and a survival advantage than PEI of lesions larger than 20 mm (15-19). RFA is, thus, currently the most popular and widely used thermal ablation modality. RFA has proved to be particularly effective for lesions smaller than 3 cm, with the best reported rate of complete necrosis approaching 99% of treated lesions, offering a 5-year overall survival of around 40% (20). A liver transplant center reported less enthusiastic data, with a histological evidence of complete response of 63% for explanted livers for HCCs with a diameter <3 cm (21). However, despite the high percentage of necrosis reported by various authors, the recurrence rate is highly variable, from 2% to 39%, depending on the technique used (22-24). Indeed for HCCs >3 cm, the success of RFA decreases, and combined therapies are adopted to increase the rate of complete ablation. RFA may not be effective within the periphery of the ablation area because of the presence of blood vessels, which can create a protective heat-sink effect (25). Combining RFA with TACE, technical success was obtained in 85% of medium-size HCCs (26, 27).
MWA has recently emerged as a new therapeutic option, offering many of the benefits of RFA with other theoretical advantages. The promised benefits of MWA are consistently wider ablation areas, faster ablation times, ability to perform multiple ablations simultaneously, and no requirement for grounding pads (9). In the past, however, the greatest limitation of microwave technology was the difficulty of obtaining spheroidal areas of necrosis due to the comet effect (6, 10). The system we used included the Amica-Probe, a coaxial antenna with a patented miniaturized device for entrapping reflected waves lodged inside a metallic introducer. This device allows for maximum control over the size and shape of the coagulative lesion, both in radial and longitudinal directions. Our preliminary data confirm that the latest generation of microwave technology is very promising. Complete necrosis was achieved in 100% of small HCC cases, with a very limited number of sessions of very short duration. The treatment of medium HCCs also showed very promising results: ablation was complete in 90% of HCCs of between 3 and 5 cm. The large volume of necrosis obtained by MWA creates a great safety margin around the lesion treated, well-evidenced by the values of Δ volume. This is reflected in the low number of local failures, especially for small and intermediate HCCs, and may be explained by the peculiar mechanism of propagation of microwave energy in tissues. While RF currents flow only in high conductivity paths, microwaves are capable of propagating through tissues with low conductivity, such as charred tissues. MWA actively heats a large, homogeneous volume around the applicator antenna, while RFA heating is limited to areas of high current density located very close to the antenna (7, 8). The other side of the coin is a hypothetical increased risk of complications due to an excessively large volume of necrosis, even if in our limited experience, we did not observe any such major complications.
In conclusion, our preliminary data show that MWA is an effective and safe ablative method. Considering the relatively short period of follow-up, we preferred not to report survival data, reserving further analysis for when such data will be available.
It would also be appreciable comparing the two most widely used methods, RFA and MWA in randomized studies, to establish which technique is superior. Moreover, the evaluation of a combined treatment of MWA and TACE in order to achieve a better rate of necrosis in lesions >3 cm should be of great interest.
The encouraging results that emerge after almost two years experience in the use of MWA certainly urge us to believe in further future development of this method.
Footnotes
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Conflicts of Interest
There are no conflicts of interest and financial disclosures.
- Received December 25, 2012.
- Revision received February 4, 2013.
- Accepted February 5, 2013.
- Copyright© 2013 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved