Stereotactic and Robotic Minimally Invasive Thermal Ablation of Malignant Liver Tumours - A Systematic Review and Meta-Analysis

doi:10.21203/rs.3.rs-110302/v1

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Stereotactic and Robotic Minimally Invasive Thermal Ablation of Malignant Liver Tumours - A Systematic Review and Meta-Analysis

https://doi.org/10.21203/rs.3.rs-110302/v1

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Background: Stereotactic navigation techniques aim to enhance treatment precision and safety in minimally invasive thermal ablation of liver tumours. We qualitatively reviewed and quantitatively summarised the available literature on procedural and clinical outcomes after stereotactic navigated ablation of malignant liver tumours.

Methods: A systematic literature search was performed on procedural and clinical outcomes when using stereotactic or robotic navigation for laparoscopic or percutaneous thermal ablation. The online databases Medline, Embase and Cochrane Library were searched. Endpoints included targeting accuracy, procedural efficiency and treatment efficacy outcomes. Meta-analysis including subgroup analyses were performed.

Results: Thirty-four studies (2 randomised controlled trials, 3 prospective cohort studies, 29 case series) were qualitatively analysed and 22 studies included for meta-analysis. Weighted average lateral targeting error was 3.7mm (CI 3.2,4.2), with all four comparative studies showing enhanced targeting accuracy compared to free-hand targeting. Weighted average overall complications, major complications and mortality were 11.4% (6.7, 16.1), 3.4% (2.1, 5.1) and 0.8% (0.5, 1.3). Pooled estimates of primary technique efficacy were 94% (89, 97) if assessed at 1 – 6 weeks and 90% (87, 93) if assessed at 6 – 12 weeks post ablation, with significant remaining between-study heterogeneity. Pooled odds ratio of primary technique efficacy for stereotactic versus free-hand targeting was 1.9 (1.2, 3.2)(n = 6 studies).

Conclusions: Advances in stereotactic navigation technologies allow highly precise and safe tumour targeting, potentially leading to enhanced early treatment efficacy. The use of varying definitions and terminology limit comparability of safety and efficacy among studies, highlighting the crucial need for further standardization of follow-up definitions.

Cancer Biology

Liver Neoplasms

Ablation Techniques

Stereotaxic Techniques

Computer-Assisted Therapies

Minimally Invasive Surgical Procedures

Thermal ablation therapy is a validated curative-intended treatment option for malignant liver tumours, mainly hepatocellular carcinoma (HCC) and liver metastases from colorectal cancer (CRLM) (1,2). Following encouraging oncological outcome results for small tumours in the setting of limited disease, thermal ablation has been introduced into international treatment guidelines for both HCC and CRLM (3,4).

The key advantage of ablative treatments is their tissue-sparing nature, allowing preservation of a maximum of functioning liver tissue, and favouring combination with a minimally invasive treatment access to further reduce procedure-related morbidity. The main challenge in achieving treatment success in such minimally invasive environments is the accurate and safe positioning of ablation probes, to acquire adequate ablation volumes with full tumour coverage(5,6). The use of (contrast-enhanced) ultrasound (US) imaging allows dynamic intraoperative tumour visualization and instrument guidance, both in surgical and interventional radiology settings(7–9). For lesions remaining invisible due to small size, deep central location, obstructing gas/ribs or changes in liver parenchyma(10), computed tomography (CT) or magnetic resonance (MR) guidance enhance visibility, but introduce constraints due to radiation exposure(11) or procedure-related complexity. Especially for tumours requiring complex targeting trajectories, such as in the liver dome or caudal lobe, a safe and efficient targeting is often precluded(12,13).

To improve tumour accessibility, targeting accuracy and treatment safety, stereotactic navigation systems have been introduced for use in minimally invasive surgery. These aim to enhance treatment precision by integrating computer-assistance with imaging data, allowing stereotactic guidance of surgical instruments (14). Over the last two decades, increasing clinical experience with commercially available navigation devices has been reported, including several summary articles highlighting their main advantages (15–21). However, no systematic review of the available literature on the clinical application of this technology exists, and the true impact on procedural and clinical outcomes remains unknown. The aim of this study was to critically review and quantitatively summarize the available literature on targeting accuracy, procedural efficiency and treatment efficacy when using stereotactic or robotic navigation technology for thermal ablation of malignant liver tumours in a minimally invasive setting.

Search strategy

This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines(22). A systematic literature review was performed on May 20^th 2020, searching the online databases MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for all available full-text articles. Search terms were organized according to the PICO criteria, without including comparison or outcome criteria to keep the search as broad as possible. Given the expected paucity of published literature, no limitation of publication dates was applied. The complete search strategy is shown in Table 1.

Study selection

Eligible studies included original articles on adults, reporting on procedural or clinical outcomes when using stereotactic or robotic guidance for targeting and thermal ablation of malignant liver tumours, using a minimally invasive (laparoscopic or percutaneous) approach. Stereotactic or robotic guidance was defined as the utilization of a tracked ablation probe or aiming device for targeting and subsequent therapeutic thermal ablation. Included studies reported on one or more of the following outcomes related to stereotactic thermal ablation of liver tumours: i) targeting accuracy, ii) procedural efficiency and safety, iii) treatment efficacy. Excluded were i) review articles, ii) conference abstracts, iii) studies focusing on image-fusion without the use of a tracked ablation probe or aiming device for tumour targeting, iv) studies analysing efficacy of combined Trans-Arterial Chemo-Embolization (TACE) and stereotactic ablation of liver tumours, v) case reports or patient series including less than 10 patients treated with navigated/robotic ablation, vi) full texts written in languages other than English.

Two authors (PT and JE) independently determined eligibility for each citation by sequential review of titles, abstracts and full texts, using the predefined criteria. Disagreements were resolved by consensus after re-assessment. Reference lists from included studies were reviewed for additional citations not identified by the original search. Covidence(23) and Mendeley were used for screening and reference citation management.

Data extraction and risk of bias assessment

All extracted data extracted for systematic review and meta-analysis were entered into a data spreadsheet available as [Additional file 1]. Main outcomes were i) targeting accuracy, defined as targeting errors resulting after stereotactic ablation probe positioning, ii) procedural efficiency and safety, including duration of the overall procedure and of stereotactic ablation probe positioning, numbers of probe readjustments, radiation exposure reported as dose length product (DLP), hospital length of stay (LOS) and clinical complications, and iii) treatment efficacy, including rates of technical success, primary and secondary technique efficacy and local tumour progression (LTP). Definitions of treatment efficacy were summarised using the standardised terminology and reporting criteria for image-guided tumour ablation(24). The authors’ detailed descriptive definitions of all endpoints are available in the [Additional file 1].

For quantitative analyses, data from studies with overlapping patient populations were obtained from the most relevant publications. These were chosen by prioritizing studies with the largest sample size and then by studies published most recently. Risk of bias in individual studies was evaluated for all outcomes according to the ROBINS-I tool(25), and studies with high risk of bias excluded from meta-analysis. Studies reporting on ablation for uncommon subpopulations of liver tumours (i.e. very large tumours) were considered high risk of selection bias toward safety and efficacy outcomes. Comparative observational studies reporting outcomes without matching of tumours with respect to targeting complexity (e.g. tumour location) were considered medium risk of bias due to confounding. Outcomes for which < 5 studies remained were excluded from meta-analysis. No quantitative analyses were performed for efficiency outcomes (probe readjustments, procedure/targeting durations) and LTP, since heterogeneity in outcome assessment across studies was deemed too important.

Data synthesis and meta-analysis

Baseline characteristics were summarised, and weighted averages, rates and odds ratios (OR) reported according to individual number of lesions or patients, as appropriate. Pooled estimates were calculated based on a modified inverse variance method, applying a continuous/binary random effects model given the assumed heterogeneity of included studies (DerSimionian-Laird method)(26). To avoid skewing of the variance towards zero, an arcsine transformation was applied for outcomes with small reported proportions (major complications, mortality)(27). Subgroup meta-analysis was performed to account for known sources of heterogeneity due to differing definitions for complications rates and primary technique efficacy. Between-study heterogeneity was reported as I² statistic and Chi-Square test of homogeneity. OpenMetaAnalyst was used for meta-analysis and generation of forest plots(28).

After screening a total of 1412 articles, 93 original works published in English and reporting on a minimum of 10 patients treated with stereotactic or robotic thermal ablation for malignant liver tumours were included for full text screening. After additional exclusion of 59 works, 34 articles were included for qualitative analysis and 22 for quantitative analysis (Figure 1).

All of the 34 included works were single-centre studies, of which 26 were retrospective studies(29,30,39–48,31,49–54,32–38), 3 prospective case series(55–57), 3 prospective cohort studies(58–60) and 2 randomised controlled trials(61,62). Two studies reported results using a laparoscopic treatment access(44,55), the other 32 reporting on thermal ablations using a percutaneous approach. Six studies applied robotic targeting using mechanical tracking(31,47,48,51,60,62), 7 an electromagnetic (EM)-tracked dynamic technique(35,42,50,55,57,59,61) and the other 21 an optically tracked stereotactic aiming device. Baseline study, patient and lesion characteristics, applied ablation and navigation techniques and reported outcomes of the included works are shown in Table 2. The published literature on stereotactic or robotic guidance for thermal ablation of liver tumours increased continuously since the first clinical series in 2011. This was the case regarding all reported endpoints, and most prominently for safety and treatment efficacy, as illustrated in Figure 2.

Targeting accuracy

Of the 34 included studies, 10 reported on targeting accuracy, of which nine reported Euclidean, lateral or angular targeting errors after stereotactic ablation probe positioning. The remaining study reported a 95.6% targeting accuracy, defined as the centre of the ablated zone being located within a 5 millimetre range from the preoperatively defined ideal target point, as assessed on a 24h CT/MRI scan(50). Pooled estimates for Euclidean, lateral and angular targeting errors were 5.3 (95% CI 3.9, 6.7), 3.7 (3.0, 4.4) and 2.4 (1.7, 3.1) millimetres, respectively, with significant between-study heterogeneity (Table 3). Summary estimates for lateral targeting errors are displayed in Figure 3.

Three studies investigated factors influencing targeting accuracy, of which two studies performed univariable between-group analyses and one group used multivariable linear regression. Mauri et al.(50) showed no influence on “correct targeting” (defined as the "Centre of the ablated zone located within 5-mm range from the ideal target point preoperatively established", as assessed on CT/MR imaging 24 hours after ablation) by tumour entity, lesion characteristics and applied guidance and ablation techniques. Widmann et al.(56) described larger lateral errors at the ablation probe tip in lesions located in “subphrenic plus fat” as opposed to “clear parenchymal” positions and in Segment II versus Segment IV. Tinguely et al.(29) reported statistically significant higher lateral targeting errors with raising targeting trajectory lengths (0.2 millimetre per additional centimetre) and when targeting tumours in cirrhotic livers (by 0.7 millimetre) in a multivariable model, with no influence shown for challenging intrahepatic lesion locations or more complex targeting trajectories.

Procedural efficiency and safety

Eighteen studies reported on procedural efficiency and all included works reported on safety related to stereotactic targeting for thermal ablation. The need for readjustment of ablation probes due to insufficient accuracy were reported varyingly across studies. Four studies reported mean numbers of ablation probe readjustments of n = 0(62), 0.8(48), 1.1(60) and 2.4(61). Nine authors reported relative numbers of probe readjustments per patients (4.8%(35), 5.6%(58), 35%(51) and 60%(48)) or per lesions (1%(29), 4%(45), 5.6%(58), 8.8%(55) and 41.2%(47)). Mean overall procedure duration ranged between 18.3 and 254.5 minutes in 12 studies, and navigated targeting duration between 1.5 and 36.3 minutes in 8 reporting studies. Mean total DLP ranged between 807 and 2216 mGy*cm in 11 studies reporting overall radiation exposure. Hospital length of stay ranged between 0 and 7 day in 18 reporting studies.

All included studies reported on treatment related complications, applying varying types of definitions. Twelve studies used the definitions proposed by the Society of Interventional Radiology (SIR)(63), 8 applied the Clavien-Dindo classification(64), 2 the definitions proposed by Ahmed et al(24), one the CIRSE classification and 11 studies used other definitions or did not further specify. The overall complication rate ranged between 0 and 57.9%, the pooled estimate being 11.4% (CI 6.7, 16.1; I² 87.9%, p < 0.01) in 16 studies included for meta-analysis. Major complications ranged between 0 and 20.5%, the 20.5% rate being reported in a study of patients undergoing stereotactic radiofrequency ablation for very large (≥ 8 cm) tumours(33). The overall pooled estimate for major complication rate was 2.4% (CI 1.4, 3.6; I²20.7%, p = 0.198), which was lower in the subgroup applying the Clavien-Dindo classification (2.0%, CI 0.7, 4.0) versus the subgroup applying the SIR classification (4.0%, CI 1.0, 8.8) (Figure 4). Mortality rates ranged between 0 and 4.3%, with a pooled estimate of 0.8% (CI 0.4, 1.4; I² 0%, p 0.99) in 20 studies included for meta-analysis.

Treatment efficacy

Thirty-one of the 34 included studies reported on treatment efficacy. Varying definitions were reported for all treatment efficacy outcomes, including the time points for assessment and the duration of follow-up. Six studies(29,31,41,42,53,61) referred to the terminology for follow-up assessment after ablation of liver tumours proposed by Ahmed et al(24), while thirteen studies applied similar definitions without explicitly referencing this classification. Individual descriptions and time points of follow-up assessments are available for each study in the Supplementary File. The varying time points and durations of follow-up assessments in studies reporting treatment efficacy are illustrated in Figure 5.

Keeping in mind this variability in definitions as well as the varying specific inclusion criteria for patients and lesions in several studies (e.g. very large tumours ≥ 8cm(33), vanishing lesions(30)), reported rates for technical success ranged from 90.2 to 100% (18 studies), for primary technique efficacy from 80.5 to 100% (27 studies) and for secondary technique efficacy from 90.2 to 100% efficacy (13 studies) and for LTP from 0 to 54% (21 studies). Quantitative analysis of primary technique efficacy (i.e. complete tumour ablation at the first follow-up imaging) according to time points of the first follow-up is summarised in Figure 3. Primary technique efficacy rates were reported higher in studies performing a first follow-up after 1 to 6 weeks (pooled estimate 93.6%, CI 88.9, 97.1), than in studies assessing primary technique efficacy at 6 to 12 weeks (pooled estimate 90.1% (CI 87.2, 92.7). Despite subgroup analysis, a statistically significant between-study heterogeneity remained in the former group (Figure 6).

Six studies presented analyses on factors influencing treatment efficacy when using stereotactic tumour targeting, four of which included multivariable regression analyses. Tinguely et al.(29) showed a statistically significant influence of tumour size (</> 3cm) and targeting accuracy (</> 5mm) on LTP, with no influence by more complex intrahepatic tumour locations, in a multivariable model accounting for clustering by using Generalized Estimating Equation (GEE). Schaible et al. reported tumour size (</> 3cm) next to the type of targeting approach (stereotactic vs. free-hand) to be a significant predictor of primary technique efficacy in a similar logistic GEE model(31). Lachenmayer et al.(41) found vessel proximity and tumour size (</> 3cm) as independent predictors for LTP. Hirooka et al.(59) reported the free-hand as opposed to the stereotactic approach to be significantly associated with “local residual recurrence” in Cox regression analysis. In univariable between-group comparisons, Widmann et al.(54) reported differences in “technique effectiveness” for lesion size </> 5cm and hollow viscera vicinity and no differences for tumour entity and lesion location. Bale et al.(52) found differences in “local recurrence” rates for lesions in proximity to vessels, bile ducts and hollow organs.

Comparative studies

Nine studies compared stereotactic versus “free-hand” ablation for varying endpoints, including two randomised controlled studies(61,62) and three prospective cohort studies(59,60) of which one matched pair-analysis(58). Main study characteristics and reported results for targeting accuracy, procedural efficiency and safety and treatment efficacy are summarised in Table 4.

Targeting accuracy was shown to be significantly enhanced when using stereotactic targeting in 3 out of 4 studies (one of them after manual adaption of the ablation probe(47)). The randomised controlled trial by Heerink at al.(62) confirmed enhanced accuracy specifically for out-of-plane trajectories (5.9 versus 10.1mm), and showed a significant reduction of ablation probe repositionings in robotic versus free-hand ablations (0 versus 1, primary study endpoint). This was confirmed by Zhang et al.(61) showing fewer instrument readjustments (2.4 versus 4.95) when using EM-guided targeting, and by Mbaliske et al.(60) when using robotic as opposed to conventional CT guidance (1.1 versus 3 readjustments).

Durations for overall procedures and for ablation probe positionings were reported variably across studies. Zhang et al.(61) showed a significant reduction in number of CT scans used for interventions (7 vs. 10), in CT fluoroscopy time and in total DLP when using EM guided as opposed to free-hand targeting. Four other studies showed a reduction, and 2 studies showed an increase in total DLP in the stereotactic versus free-hand cohort using (Table 2). In the RCT of Heerink et al.(62), the number of navigational CT scans tended to be lower in stereotactic versus free-hand procedures (5 versus 7), and the increase in DLP was presumably due to the larger scan field necessary to include the optical reference fiducials.

With respect to treatment efficacy, Zhang et al.(42) showed a higher complete ablation rate in the first session (3 days after ablation) when using stereotactic EM guidance, but equal primary technique efficacy at 1 month. Schaible et al.(31) reported a significantly higher primary technique efficacy when using robotic targeting in a retrospective comparative study. The pooled odds ratio for stereotactic versus free-hand targeting was 1.94 (CI 1.18, 3.19) (Figure 7). All six studies included in this meta-analysis assessed primary technique efficacy at a first follow-up imaging between 1 and 6 weeks.

Four propensity score matched analyses compared stereotactic thermal ablation for different subtypes of patients or lesions. Stereotactic RFA yielded similar safety and treatment efficacy outcomes when comparing CT ‘invisible’ tumours ablated with MR image fusion to CT visible tumours(30), octogenarians to a younger study population(36), lesions in a subphrenic location to non-dome locations(39) and HCC in a subcardiac position to a non-subcardiac location(40).

This work is a summary of the currently published knowledge on procedural and clinical benefits of applying minimally invasive stereotactic and robotic navigation technology for thermal ablation of malignant liver tumours. To our knowledge, this is the first systematic review and meta-analysis on this topic.

Stereotactic navigation technologies for use in liver surgery aim to enhance precision when performing tissue sparing treatments such as “atypical” resections not following standard anatomical landmarks or locally targeted interventions such as thermal ablations. For the latter case specifically, the aims are to i) ensure adequate oncological results in a minimally invasive setting by precise ablation probe positioning, and to ii) enhance safety by defining trajectories that avoid injury to critical anatomical structures. Stereotactic navigation systems enable quantification of the accuracy with which ablation probes are positioned, by measuring the error between the planned “optimal” and the final “real” probe position. This facilitates the intraoperative decision regarding an eventual probe readjustment and importantly, allows a reproducible and comparable evaluation of targeting success. As summarised herein, pooled estimates for targeting accuracy in over 650 targeted lesions ranged from 2.4 to 5.3 mm, with relatively small confidence intervals and with all comparative studies showing reduced targeting errors as compared to free-hand techniques (Table 4). On the basis of this unanimously enhanced targeting precision, an increasing number of works focused on reporting concurrent safety, efficiency and efficacy in the last three years.

The pooled estimates for major complication rates for different definitions ranged between 1.8 and 5.2%, as expected when applying tissue sparing treatments in a minimally invasive setting. Importantly, the number of probe readjustments was significantly reduced in three comparative studies, including two randomised controlled trials. This decrease in liver punctures until reaching adequate probe positions toward n = 1 represents an important virtue of stereotactic thermal ablation potentially leading to enhanced safety(60,62). The high efficiency in tumour targeting did not unanimously translate into reduced overall procedure durations, where confidence intervals were wide and conflicting results were reported in comparison to free-hand targeting. An increased complexity in hardware set-up and procedural workflows have been highlighted as potential drawbacks when using such novel technology(48). One way to optimize procedural efficiency when applying such novel technology is to invest in initial training of staff including anaesthesia, to create smooth and standardized clinical workflows in multidisciplinary teams. The latter allow relatively steep learning curves(44) and a reduction of inter-operator variance as a factor influencing outcomes after thermal ablation(54). The present study confirms enhanced reliability and reproducibility of outcomes as being one of the key advantages of using stereotactic ablation techniques(34).

Overall reported treatment efficacy rates were encouraging, leading to increased early local tumour control when using stereotactic navigation as opposed to manual guidance as shown in the latest available comparative studies (Figure 7). Of importance is the inconsistency in reported definitions describing technique efficacy and LTP (Figure 5). While standardized terminology and reporting of outcomes criteria after image-guided ablation have been proposed(24), definitions allow wide ranges of author-dependent interpretations. Especially the definition of “secondary treatment efficacy” allows for differing and unspecified numbers of retreatments over an undefined follow-up period to be included. Consequently, detectable tumour at the ablation site might only be defined as “local tumour progression” rates after 6 or 12 months after the initial ablation. This renders a straight-forward comparison of reported results impossible. Despite subgroup meta-analysis according to time point of follow-up, subgroups remained highly heterogenous due to variations in included patients, lesions and applied types of stereotactic ablative treatments. This highlights the need for further standardization of follow-up definitions toward more clearly defined ranges of follow-up time points and more precise terminology. Using novel segmentation technology, a quantitative volumetric assessments of ablation margins will in the future allow a quantified distinction between “incomplete ablation” and true “tumour recurrence/progression at the ablation site” (65). Integrating such precise assessment of treatment success into refined follow-up terminology could contribute to the generation of more reproducible and comparable outcomes after stereotactic thermal ablation.

Varying types of navigation modalities were applied in the included studies, such as optically tracked aiming devices or EM tracked ablation probes combined with US to CT/MR image fusion. An upcoming group of navigation systems use robotic assistance devices, relying on mechanical tracking for automatic orientation of the robotic arm but still requiring manual insertion of ablation probes. These comprise important but only initial steps towards automation and standardization of stereotactic ablation on a larger scale. Future generations of robotic devices aim to perform automated probe positioning according to defined trajectories(66) and generate individualized ablation volumes for specified tumour configurations(67). The development of automated and dynamic patient tracking will further allow to address current challenges related to motion artefacts and facilitate ablation under sedation. No clear benefit regarding targeting accuracy when using current robotic versus non-robotic approaches can be confirmed to date.

A limitation of the present work involves the heterogeneity in tumour types and in applied ablation systems in the included studies, since the variability in the response to applied ablation energies across tumour types and devices are known(68,69). Additionally to the aforementioned heterogeneity in definitions of treatment efficacy endpoints, a variability in the calculation of morbidity and mortality rates (assessment per patient vs. per intervention vs. per lesion, 30 vs. 90-day period) remained. In some studies it was further unclear if the positioned ablation probes, for which targeting accuracies were reported, were the ones applied for subsequent thermal ablation. This might affect conclusions regarding a relationship between targeting accuracy and resulting treatment efficacy. Accurate tumour targeting represents the essential initial step for successful ablation of liver tumours, and an independent correlation with early ablation site recurrence has been described(29). However, many other important tumour-specific determinants affect ablation site recurrences, such as satellite nodules detectable on pathology but not imaging, recurrence risk determined by underlying liver disease, mutational status and location of primary tumour, and different types and time points of chemotherapy regimens(70,71). This underlines the difficulty of comparing treatment efficacy after a certain, currently undefined period of time after thermal ablation of liver tumours between individual studies, which should be avoided.

As technology evolves, it can be expected that stereotactic and robotic interventions will increasingly become an integral part of the multimodality management of malignant liver tumours. Due to the increasing expertise in specialized centres, treatment indications for stereotactic thermal ablation are increasingly expanded. The present summary shows the encouraging results in all reported outcomes including for patients with tumours in difficult intrahepatic locations (centrally, liver dome(39), segment 1(37)), very large tumours(33) and “vanishing” or CT invisible tumours using image fusion(72). In practice, minimally invasive stereotactic ablation approaches are beneficial especially in these situations, where they allow a curative intended treatment when conventional image guidance techniques preclude an efficient and safe targeting. Key challenges remaining to be addressed when using current navigation technology are potential inaccuracies due to motion artefacts(73) and concerns regarding cost effectiveness(74).

Advances in stereotactic navigation technology allow highly precise, safe and efficient minimally invasive ablation of malignant liver tumours, potentially leading to enhanced early treatment efficacy compared to traditional guidance techniques. Heterogeneity in terminology and time points in follow-up assessment severely limits comparability of safety and treatment efficacy among studies, highlighting the crucial need for further standardization and guidelines for follow-up definitions.

Ethics approval and consent to participate

Not applicable

Consent for publication

Not applicable

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary information files [Additional file 1].

Competing interests

The authors declare that they have no competing interests.

Funding

Pascale Tinguely reports funding from the Prof. Dr. Max Cloëtta Foundation, Switzerland, and from the Swiss Cancer League (BIL KLS-4894-08-2019).

Jennie Engstrand was supported by Region Stockholm (clinical postdoctoral appointment) and funded by Ruth and Richard Julin Foundation.

Sources of funding had no involvement in study design, data collection/analysis or manuscript preparation.

Authors contributions

Authors PT and IP were involved in study concept and design, data acquisition, data analysis and interpretation, statistical analysis and manuscript preparation and editing.

Authors SR and JE were involved in study concept and design, data analysis and interpretation and manuscript editing and review.

Authors SW, KJ, DC and JF were involved in study concept and design and manuscript editing and review.

All authors have made a significant contribution to this manuscript, have seen and approved the final manuscript and have agreed to its submission to the BMC Cancer.

Acknowledgements

Not applicable

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Table 1: Search strategy

Specification	Population	AND	Intervention (Part 1)	AND	Intervention (Part 2)	AND	Comparison / Outcome
	Patients with liver tumors		Stereotactic		Thermal ablation		Accuracy, efficiency, efficacy
Text word search (Medline and Embase)	liver:tiab		stereota*:tiab		ablation:tiab		Not applied
	hepatic:tiab		navigat*:tiab
			robot*:tiab
Thesaurus search MeSh (Medline, Cochrane Library)	liver neoplasms		computer-assisted therapy		ablation techniques
			stereotaxic techniques		radiofrequency ablation
Thesaurus serach Emtree (Embase)	liver cancer/exp		stereotactic treatment/exp		ablation therapy/exp
	liver metastasis/exp		robot assisted surgery/exp

Boolean Operators “OR” applied between search terms (rows) within PICO columns and “AND” between PICO columns. :tiab: Title and abstract. /exp: explosion search

Table 2: Baseline characteristics of included studies

Study, year published

Study design

Tumor entity

Lesion subgroup

N patients

N lesions

Lesion size [mm] °

Ablation technique

Imaging technique

Tracking technology

Navigation device

Anesthesia

Ventilation

Outcomes reported and data overlap/risk of bias ^#

HCC

Metas

CCC

Acc

Eff ^#

Saf

Eff

TinguelyA, 2020

153

301

MWA

Optical

CAS-ONE ^a

General

Jet-Vent

1 ^#

SchullianA, 2020

CT-invisible

199

HCC: 29
Metas: 25

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

Schaible, 2020 *

not defined

249

18.8

MWA

Mechanical

MAXIO ^c

General

Tube discon

1 ^#

SchullianB, 2020

Previous resection

140

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

SchullianC, 2020

Size > 8 cm

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

SchullianD, 2020

Multiple n ≥ 4

549

2.7

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

Volpi, 2019

Not visible on US

RFA/MWA

IMACTIS ^d

General

Jet-Vent

1 ^#

SchullianE 2019

Octogenarians

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

SchullianF, 2019

Caudate lobe

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

Perrodin, 2019

Non- CRLM

13.5

MWA

Optical

CAS-ONE^a

General

Jet-Vent

1 ^#

SchullianG 2019

Hepatic dome

177

238

RFA

Optical

Stealth Station Treon plus^b

General

Tube discon

1 ^#

SchullianH 2019

Subcardiac

114

MWA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

ZhangA, 2019

RCT

Solitary nodule

≤ 5cm

RFA/MWA

IG4 ^e

Local/sedation

1 ^#

Lachenmayer, 2019

174

MWA

Optical

CAS-ONE^a

General

Jet-Vent

1 ^#

Heerink, 2019 *

RCT

1 +

Benign

N ≤ 3

≤ 5cm

21.2

MWA

Mechanical

Needle Positioning System ^f

General

Tube discon

1 ^#

BeyerA, 2018

20.6

MWA

Optical

CAS-ONE ^a

General

Tube discon

1 ^#

ZhangB, 2018

N = 1

3 - 8 cm

41.4

MWA

CT/US

Fusion image navigation system ^g

General

1 ^#

BaleA, 2017

Mamma CA

2.8

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

TinguelyB, 2017

346

16.7

MWA

Preoperative CT

Optical

CAS-ONE^a

General

Tube discon

1 ^#

Hirooka, 2017

P cohort study

N = 1

≤ 5cm

23.9

Bipolar RFA

CT/US

3D sim-Navigator^h

General

Engstrand, 2016

Invisible on US

N ≤ 2

≤ 3cm

14.9

MWA

Optical

CAS-ONE ^a

General

Jet-Vent

1 ^#

BaleB, 2016

Melanoma

≤ 5cm

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

BeyerB, 2016 *

not defined

19.1

MWA

Mechanical

MAXIO ^c

General

Apnea

1 ^#

AbdullahA, 2015 *

RFA/MWA

Mechanical

MAXIO^c

General

Tube discon

1 ^#

Mbaliske, 2014 *

P cohort study

N = 1
Prior TACE (3 months)

23.2

MWA

Mechanical

MAXIO^c

Local/sedation

1 ^#

Sindram, 2014

18.0

MWA

AIM Guidance System ⁱ

General

1 ^#

SchullianI, 2014

Prior laparoscopic liver packing

120

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

Mauri, 2014

Not/incompletely visible on US/ CEUS

175

295

RFA/MWA

US-CT
US-MRI

VirtuTrax ^j

General

Tube discon/ end-exp

Abdullah,B 2013 *

21.8

RFA

Mechanical

ROBIO EX ^c

General

Tube discon

1 ^#

BaleC, 2011

189

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

Haidu, 2011

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

1 ^#

WidmannA, 2011

N ≤ 7

≤ 12cm

177

RFA

Optical

Stealth Station Treon plus ^b

General

Tube discon

WidmannB, 2011

not defined

RFA

Optical

Stealth Station Treon plus^b

General

Tube discon

Liu, 2011

US: invisible

CT/MRI: yes
≤ 3 nodules

18.5

MWA

US-CT
US-MRI

MyLab90 System, Virtual Navigator ^k

Local/sedation

1 ^#

TOTAL

1531

3806

*Robotic guidance. °Median or average, as reported.^#Excluded from meta-analysis.

^aCAScination AG, Switzerland, ^bMedtronic, USA, ^cPerfint Healthcare, India, ^dImactis, France, ^eVeran Medical Technologies Inc, USA, ^fDEMCON Advanced Mechatronics, Netherlands, ^gSelf developed, ^hHitachi Healthcare, Japan, ⁱInnerOptic Technology Inc., USA, ^jCIVCO Medical Solutions, USA,^kEsaote SpA, Italy.

RCT Randomized controlled trial, R Retrospective, P Prospective, HCC Hepatocellular carcinoma, CRLM colorectal cancer liver metastases, CCC Cholangiocellular carcinoma, CEUS Contrast-enhanced ultrasound, TACE Transarterial chemoembolization, RFA Radiofrequency ablation, MWA Microwave ablation, DLP Dose length product, EM electromagnetic

Table 3: Summary of targeting accuracy

Study, year published	Euclidean error [mm]	Lateral error [mm]	Angular error [°]
TinguelyA, 2020		2.9 ± 2.3	2.0 ± 1.2
Volpi, 2019	22 ± 19 °
Heerink, 2019 *	10.2 ± 5.2	6.4 ± 4.2	4.5 ± 3.2
BeyerA, 2018	3.7 ± 1.2	2.8 ± 1.3	2.7 ± 1.5
Engstrand, 2016	5.8 ± 3.2	4.0 ± 2.5	2.7 ± 2.9
BeyerB, 2015 * ^#	3.1 ± 2.5
Mbaliske, 2014 * ^#	5.3 ±1.8
WidmannB, 2011		3.6 ± 2.5	1.3 ± 1.2
Pooled estimates (95% CI)	5.3 (3.9, 6.7)	3.7 (3.0, 4.4)	2.4 (1.7, 3.1)
Heterogeneity (I^2, p-value)	(92.6%, <0.001)	(75.3%, 0.003)	(83.9%, <0.001)

* Robotic guidance

^#Only accuracies of initial probe placements are shown (before eventual re-adjustments)

° Defined as “first-pass control”: aiming at approximately 1 cm from the tumor. Not included in weighted average

Table 4: Comparison of stereotactic versus free-hand ablation targeting for thermal ablation

Study

Study design

Matching method

N patients (lesions) stereotactic cohort

Ablation technique

Main outcomes (stereotactic versus control group)

Targeting errors

N probe readjustments

N skin punctures

Overall procedure time

Targeting time

Total DLP

Complications

Primary technique efficacy

Local tumor progression

Schaible 2020 *

None

(Regression analysis)

? (246)

MWA

ns (¯)

↑

ZhangA, 2019

RCT

n/a

20 (20)

RFA

MWA

ns (¯)

ns (↑)

Heerink, 2019 *

RCT

n/a

31 (47)

MWA

ns (↑)

↑

ns (¯)

BeyerA, 2018

(R manual cohort)

Matched pairs

18 (18)

MWA

ns (¯)

ns (↑)

ZhangB, 2018

None

19 (19)

MWA

↑

ns (↑)

↑ first session

ns (¯)

Hirooka, 2017

P cohort study

None

27 (27)

Bipolar RFA

ns (¯)

BeyerB, 2015 *

None

? (34)

MWA

ns (¯)

¯ after manual correction

ns (¯)

AbdullahA, 2015 *

None

20 (40)

RFA

MWA

ns (↑)

Mbaliske, 2014 *

P cohort study

None

30 (30)

MWA

↑

*Robotic guidance. RCT Randomized controlled trial, R Retrospective, P Prospective, HCC Hepatocellular carcinoma, CRCLM colorectal cancer liver metastases, CCC Cholangiocellular carcinoma, RFA Radiofrequency ablation, MWA Microwave ablation, DLP Dose length product, ns non-significant, ↑¯ statistically significant differences, (↑¯) statistically non-significant differences

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File name: Additional file 1 File format: Excel sheet (.xlsx) Title of data: Extracted data Description of data: All data extracted for systematic review and meta-analysis
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File name: Additional file 1 File format: Excel sheet (.xlsx) Title of data: Extracted data Description of data: All data extracted for systematic review and meta-analysis

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Stereotactic and Robotic Minimally Invasive Thermal Ablation of Malignant Liver Tumours - A Systematic Review and Meta-Analysis

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