Introduction
Colorectal cancer is the third most common malignancy worldwide and the second most common cause of cancer death in developed countries [
1]. Approximately 50 % of patients develop colorectal liver metastases (CRLM), yet only a minority (10–15 %) is feasible for hepatic resection. Five-year survival after liver resection ranges between 31 and 58 % in carefully selected patients [
2,
3]. Thermal tumour ablation, especially radiofrequency (RFA) and microwave ablation (MWA), is commonly employed and widely available. Five-year survival following RFA varies between 17 and 51 % [
4]. The long-term results of RFA are well reported and demonstrate an excellent safety profile and good primary efficacy rate and assisted efficacy rate for small CRLM [
5‐
7]. RFA is considered less suitable for lesions in close proximity to large vessels because of the so-called ‘heat-sink’ effect, where heat is carried away by the flowing blood, leading to higher local site recurrence rates. MWA does not rely on the passive conduction of heat and therefore is often preferred over RFA for perivascular CRLM [
8,
9]. However, microwave systems also face several limitations including shaft heating, large diameter probes, less predictable ablation zones, and higher peak temperatures with the potential hazard of occluding important vessels or damaging vital structures such as the major bile ducts [
8,
10].
The primary aim of this study was to retrospectively analyse the safety and efficacy of RFA versus MWA in the treatment of unresectable CRLM in proximity to large vessels and/or major bile ducts.
Discussion
There is surprisingly little literature comparing RFA with MWA for CRLM. There are no series available that make a direct comparison between the two techniques. Although local site recurrence rates and established survival outcomes after RFA or MWA seem similar, apparent inclusion and exclusion biases make it difficult to perform a fair meta-analysis. In the treatment of hepatocellular carcinoma, the vast majority of studies showed either an equivalent role for both techniques or an upper hand for MWA [
15‐
23].
In RFA, an alternating electrical circuit is created through the body to conduct RF current. Because of the abundance of ionic fluid present, RF current is able to pass through tissue. However, as tissue is not a perfect conductor, the current causes resistive heating (the Joule effect). MWA represents a specific form of dielectric heating, where the dielectric material is tissue. Dielectric heating occurs when an alternating electromagnetic (EM) field is applied to an imperfect dielectric material. In tissue, heating occurs because the EM field forces water molecules in the tissue to oscillate. The bound water molecules tend to oscillate out of phase with the applied fields, so some of the EM energy is absorbed and converted to heat [
24]. MWA has several theoretical advantages that may result in improved performance near blood vessels. Owing to the much broader field of power density (up to 2 cm surrounding the antenna), MWA results in a larger zone of active heating. Active RF heating occurs within several millimetres surrounding the electrode and heat distribution is primarily based on passive conduction. The increased zone in MWA allows for a more homogeneous zone of tumour cell death, both within the targeted zone and next to blood vessels. This feature is thought to make MWA less affected by heat sink, although our results contradict this assumption. We only included patients treated with the first generation MWA system employing 915 MHz. Recent developments in the field of MWA, employing higher frequency bands (2.45 GHz) or spatial energy control (thermal, field and wavelength), claim to create more predictable, larger and more spherical ablation zones [
22]. Other ablation technologies include high-intensity focused ultrasound, cryoablation and laser ablation. Limited data are available concerning their efficacy and safety profile [
25]. Potential disadvantages of cryoablation include cryoshock and the risk of bleeding complications due to the lack of cautery effects and coagulation of injured vessels. The specific efficacy and safety is currently being investigated [
26]. In the near future, irreversible electroporation may prove to have a superior safety profile and a higher efficacy for perivascular lesions because cell death is induced using electrical energy and primarily non-thermal [
27].
In the treatment of CRLM, resection is still considered the gold standard by most [
28‐
30]. However, given the large number of studies reporting similar survival after thermal ablation for unresectable lesions, it seems conceivable to merely consider surgical resection the historical standard [
5‐
7,
28‐
30]. Descriptive series comparing outcome in survival between focal therapies such as surgical resection, RFA, MWA and others are by definition eclipsed by selection bias. The issue of recurrence in the treatment with RFA has been of great importance, especially in lesions located near large vessels due to the heat-sink effect. Reported local recurrence rate ranges widely, from 2 to 60 %. In the presented study that included merely perivascular CRLM, the local control rate of 86 % advocates the use of thermal ablation for unresectable lesions, especially considering that many uncontrolled lesions were not retreated simply due to extensive recurrence elsewhere, making local (re)treatment biologically futile. The 5- and 10-year OS of 54 and 25 % for the entire group seems competitive to the reported outcomes after surgical resection and once again promotes the setup of a randomized controlled trial comparing surgical resection to thermal ablation [
30]. However, in the absence of this trial, thermal ablation should still be reserved for unresectable CRLM.
This comparative multivariate analysis did not detect a difference in primary efficacy rate after 12 months nor in assisted efficacy rate for RFA versus MWA in treating perivascular and peribiliary CRLM. These results seem to conflict with the broadly adopted assumption that MWA is superior to RFA for perivascular lesions. The difference in primary efficacy rate after 3 and 12 months between RFA and MWA remains unclarified. Hypothetically, differences between the groups regarding adjuvant chemotherapy, biological aggressiveness and physiological differences in the peri-ablative inflammatory response can lead to later detection of site recurrences. However, for the RFA group the number of synchronous metastases was higher and the number of patients receiving (neo)adjuvant chemotherapy lower. Compared to RFA, MWA is a weak stimulator of local inflammation [
30]. Theoretically, the greater local inflammatory response after RFA can make early diagnosis of residual or recurring disease more difficult on
18F–FDG– PET. Furthermore, residual vital tumour cells may have been temporary suppressed by the local IL-1- and IL-6-mediated immune response after RFA [
31]. Complication rate and severity was higher for peribiliary lesions treated with MWA, although overall complication rates were low for both ablation techniques. Although the lower operator experience for the more recently introduced MWA technique could have confounded results, for both groups, the number of complications did not decrease with experience.
The study is strengthened by long-term follow-up information. Data were collected from a prospective registry that covers all metastatic colorectal cancer patients treated with thermal ablation in a high-volume single centre by two interventional radiologists with broad experience in ablation. The rationale for this strategy was the fact that MWA is nowadays promoted as superior to RFA for perivascular lesions and RFA is thought to represent a safer option for peribiliary CRLM because of the less aggressive heat production and superior ablation zone predictability. We chose primary and assisted efficacy rate as primary endpoints, because this represents a reliable and objective outcome measure for focal therapies pursuing cure. Given the superior sensitivity of intraoperative ultrasound (IOUS) to detect additional small CRLM, most lesions were treated using an open approach. Over the last decade, the accuracy of preoperative radiological staging has improved by using high-quality cross-sectional imaging techniques such as MRI with hepatospecific contrast agents and diffusion-weighted imaging. These developments may have reduced the importance of IOUS as staging technique. Nevertheless, even in centres employing state-of-the-art pre-procedural imaging, intraoperative findings still alter the course of the procedure in a considerable number of patients [
32‐
35]. Furthermore, many patients underwent combined ablations plus resection(s) of CRLM and/or their primary tumour in a single session. Although the percutaneous approach is indisputably superior to the open approach regarding safety and invasiveness, the open approach is still thought to be superior regarding local efficacy [
36,
37]. New techniques to improve visualization during percutaneous ablations, such as PET/CT-guided percutaneous ablation and US-CT/MRI image fusion, are promising [
38‐
40]. We used
18F-FDG PET for follow-up in all patients, which is widely considered to represent the most sensitive technique to detect recurring disease [
41].
Conclusions drawn from this retrospective series are most limited by the fact that we compared two historical cohorts with an inherent selection bias for lesions treated in the more recent era where both techniques were available. The groups were relatively small, especially given the low number of local site recurrence and complications for both groups, which enhances the possibility that our findings result from chance. The assisted efficacy rate should also be interpreted with care. Results after retreatment were assessed regardless of the type of retreatment, allowing a crossover from RFA to MWA and vice versa. However, only 6/52 recurrences were retreated using the alternate thermal ablation technique. Furthermore, the two historical cohorts obscure the use of survival as primary measure, because results may be confounded by more advanced systemic therapies. The optimal study design to assess the efficacy of the two techniques would be a prospective randomized controlled trial. Various attempts in history demonstrate the difficulties in setting-up and completing well-designed comparative studies for local therapies. For focal ablation, novel and supposedly improved methods appear with high frequency. They are introduced into general practice as part of standard care because selection of patients seems intuitive. The touted reasons are mostly theoretical and practical. Conducting randomized controlled trials has proven exceedingly difficult. As a consequence, no hard data have ever shown a clear oncological benefit of one ablation technique over the other. On the other hand, this study demonstrates that the assumption of superiority of MWA compared to RFA for perivascular lesions may have been precipitated, although the comparable outcome is reassuring. Long-term (10-year) follow-up could not be assessed for the MWA group since it was first used in our institution in 2007.
To conclude, RFA and MWA can be considered safe treatment options that appear to have equal efficacy for unresectable perivascular CRLM. Thermal ablation in the vicinity of major bile ducts seems effective although major complications can occur. Given the similar efficacy rate and lower complication rate, it is advised to use RFA instead of MWA for lesions that are located in the vicinity of the main bile ducts.