Radiofrequency ablation (RFA) has been recognized as first line treatment for very early-stage hepatocellular carcinoma (HCC) (lesion diameter <2 cm) and is used as treatment for unresectable early-stage HCC (solitary lesion, or a maximum of 3 lesions with a diameter ≤3 cm each), according to the Barcelona Clinic for Liver Cancer (BCLC) staging system [
After RFA treatment, two types of intrahepatic recurrences may occur. Local tumor progression (LTP) is found in up to 50% of ablations [
The preferred treatment for early-stage HCC is surgical resection. However, many patients are not eligible for this treatment, due to cirrhosis with portal hypertension, unfavorable tumor location, and/or comorbidities [
Histological confirmation of total tumor necrosis after RFA is not possible. In many centers, the current workflow involves qualitative assessment of RFA margins by scrolling through pre- and postinterventional images, separately. Technical success is considered when a predefined amount of energy is successfully delivered to the tumor, and complete tumor coverage with sufficient ablative margins is confirmed on contrast-enhanced computed tomography (CECT) [
Supportive ablation verification software has gained interest. However, at this moment, software dedicated to quantitative ablation margin assessment is lacking and available software has not been validated in large patient cohorts. Merging of pre- and postablation scans can be performed using either nonrigid or rigid coregistration software. Nonrigid coregistration algorithms allow more degrees of freedom in the transformation to fit a scan better onto another. Besides global linear transformations, like translation and rotation, the algorithm may, e.g., use radial basis functions or other free form deformation models that allow for local warping of the image to find a better registration. Mirada RTx (Mirada Medical Ltd., Oxford, UK) is a software application developed for radiation therapy treatment planning that uses nonrigid registration of medical image datasets including computed tomography (CT) and magnetic resonance imaging (MRI). This software was used in this study.
The primary objective of this study was to assess the feasibility of quantitative three-dimensional (3D) margin assessment after nonrigid CT-CT coregistration of pre- and postinterventional imaging, using Mirada RTx. Secondary objectives were to compare quantitative ablative margin assessment with the current workflow of qualitative assessment and to assess whether quantitative assessment allows prediction of local tumor progression.
All patients that were consecutively treated with RFA for de novo HCC between January 2009 and March 2014 (
Characteristics of analyzed patients.
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||
---|---|---|
Total | 25 | |
Age | ||
Mean (SD) | 62, 1 | 11.8 |
Sex | ||
Male | 20 | 80.0% |
Female | 5 | 20.0% |
Cirrhosis presence | ||
Yes | 25 | 100.0% |
No | 0 | 0.0% |
Ascites presence | ||
Yes | 7 | 28.0% |
No | 18 | 72.0% |
Etiology | ||
Hepatitis B | 2 | 8.0% |
Hepatitis C | 8 | 32.0% |
Alcohol abuse | 15 | 60.0% |
NASH | 2 | 8.0% |
Cryptogenic | 1 | 4.0% |
ECOG | ||
0 | 24 | 96.0% |
1 | 1 | 4.0% |
Child–Pugh score | ||
A | 12 | 48.0% |
B | 13 | 52.0% |
C | 0 | 0.0% |
BCLC | ||
Very early | 10 | 40.0% |
Early | 15 | 60.0% |
Lesion size (mm) | ||
Median (range) | 20 | 12–45 |
Year of RFA | ||
2009–2011 | 10 | 31.3% |
2012–2014 | 15 | 46.9% |
NASH = nonalcoholic steatohepatitis; ECOG = Eastern Cooperative Oncology Group; BCLC = Barcelona Clinic for Liver Cancer; RFA = radiofrequency ablation. More etiological factors could be present in one patient.
Percutaneous RFA procedures were performed under general anesthesia and with image guidance of ultrasound and/or CT. Based on tumor size and availability, one of the single electrode RFA systems (3 cm exposed tip Cooltip (Covidien Ltd., Gosport, Hampshire, United Kingdom)) or StarBurst XL (AngioDynamics, Amsterdam, Netherlands)) or multiple electrode RFA systems (3 or 4 cm exposed tip Cooltip with switch control system (Covidien Ltd.)) was used. The ablation time was set 12 minutes for single Cooltip electrode and 16 minutes for the multiple Cooltip electrodes. Temperature-based ablation was performed with the StarBurst XL electrode.
Immediately after ablation, a CECT scan of the liver was performed on a 16-slice spiral CT (Aquilion-16, Toshiba, Tokyo, Japan) with the following settings: 120 kV, rotation 0.5 s, and 16 × 1 mm scanning. Dose weight-dependent Ultravist 370 contrast agent or Xenetix 350 contrast agent was used with a 15-second and 75-second delay after bolus triggering for arterial phase and portal venous phase, respectively. Consequently, the CECT scans were qualitatively evaluated for technical success. The ablation was considered technically successful if the coagulation area fully encompassed the tumor in the absence of residual tumor enhancement. This assessment was done by visual comparison of the tumor location on preprocedural CT and area of necrosis on the postprocedural CT (“eyeballing”) and 2D measurements.
All patients underwent blood tests (including alpha-fetoprotein) and CECT every three months after treatment. Upon discretion of the referring physician or interventional radiologist, multiphase MRI was used instead of CECT. Liver explants of patients that underwent an orthotopic liver transplantation (OLTx) were pathologically examined for local tumor progression. The median follow-up time was 9.5 months.
CT-CT registration and delineation of the tumor volume and RFA ablation volume were performed in Mirada RTx software. Two radiologists independently performed the CT-CT coregistration and delineation of the tumor and RFA ablation volume, while being blinded for follow-up information. CT-CT coregistration was performed using a semiautomated nonrigid registration. Manual alterations were possible by rotation and translation of a scan or with use of a rigid landmark algorithm. The registration performance was graded on a 5-point scale (1 = completely unreliable coregistration; 2 = suboptimal coregistration; 3 = sufficient quality of coregistration, but not accurate enough for measurements in mm; 4 = good coregistration; 5 = perfect coregistration). Patients with coregistration performances of 1–3 were excluded from further analysis.
A greyscale-based semiautomatic delineation tool was used with manual adjustments for segmentation of the tumor and ablation volume. RFA margins were quantitatively assessed in a fused image window. The narrowest margin (in mm) as well as the anatomical location of the narrowest margin or largest tumor residue was determined. Interobserver agreement was determined for the categorical assessment of margin size (1: negative, 2: 0 to 5 mm, or 3: ≥5 mm). A “negative” margin was defined as tumor extending beyond the boundaries of the ablation zone on the overlay of pre- and postablation CT. This would not necessarily mean that the tumor was incompletely ablated. The ablation may have caused tissue shrinkage, and as a result, the ablation area may be smaller than the tumor even when the tumor was completely ablated. The side of LTP occurrence was correlated with the side of the minimal ablative margin or largest tumor residual. A comparison of patient characteristics between those with and without LTP was performed.
Two other radiologists independently repeated the qualitative assessment of the pre- and postablation scans for technical success and determined categorical ablative margins (1: negative, 2: 0 to 5 mm, or 3: ≥5 mm), while being blinded for follow-up information. Also, the anatomical side of narrowest margin was recorded. Interobserver agreement rates were determined for technical success and margin size. In both the quantitative and the qualitative assessment, a consensus reevaluation took place by the two radiologists for determining technical success for cases they initially disagreed on.
Interobserver agreement was determined with use of unweighted Cohen’s kappa statistics. A
Continuous data were analyzed with the independent
The coregistration quality of pre- and postablation scans was rated ≤3 in 7/25 (28.0%) patients, who were therefore excluded for further analysis. Table
Characteristics of patients technically feasible for quantitative analysis.
Total | No LTP | LTP | |||||
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Total |
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10 | 8 | ||||
Age | |||||||
Mean (SD) |
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66.1 (10.7) | 63.4 (6.5) |
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Sex | |||||||
Male |
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7 | 70.0% | 7 | 87.5% |
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Female |
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3 | 30.0% | 1 | 12.5% | |
Cirrhosis presence | |||||||
Yes |
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10 | 100.0% | 8 | 100.0% | |
No |
|
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0 | No | 0 | 0.0% | |
Ascites presence | |||||||
Yes |
|
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3 | 30.0% | 2 | 25.0% |
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No |
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7 | 70.0% | 6 | 75.0% | |
Etiology | |||||||
Hepatitis B |
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0 | 0 |
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Hepatitis C |
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2 | 2 |
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Alcohol abuse |
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2 | 3 |
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NASH |
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2 | 0 |
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ECOG | |||||||
0 |
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10 | 100.0% | 7 | 87.5% |
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1 |
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0 | No | 1 | 12.5% | |
Child–Pugh score | |||||||
A |
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5 | 50.0% | 4 | 50.0% |
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B |
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5 | 50.0% | 4 | 50.0% | |
BCLC | |||||||
Very early |
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3 | 30.0% | 3 | 37.5% |
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Early |
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7 | 70.0% | 5 | 62.5% | |
Lesion size | |||||||
Median in mm (range) |
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22 (12–27) | 22 (16–25) | ||||
OLTx <18 months | |||||||
Yes |
|
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3 | 30.0% | 3 | 37.5% |
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No |
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7 | 70.0% | 5 | 62.5% | |
Distant intrahepatic recurrence | |||||||
Yes |
|
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1 | 10.0% | 0 | 0.0% |
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No |
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9 | 90.0% | 8 | 100.0% | |
RFA on target quantitative assessment | |||||||
Yes |
|
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6 | 60.0% | 0 | 0.0% |
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No |
|
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4 | 40.0% | 8 | 100.0% | |
RFA on target qualitative assessment | |||||||
Yes |
|
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10 | 100.0% | 6 | 75.0% |
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No |
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0 | 2 | 25.0% | ||
Year of RFA | |||||||
2009–2011 |
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2 | 20.0% | 5 | 62.5% |
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2012–2014 |
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8 | 80.0% | 3 | 37.5% |
NASH = nonalcoholic steatohepatitis; ECOG = Eastern Cooperative Oncology Group; BCLC = Barcelona Clinic for Liver Cancer; RFA = radiofrequency ablation. More etiological factors could be present in one patient.
The interobserver agreement for
The interobserver agreement of two radiologists who
In 8 out of 18 patients (44.4%), LTP was found, either radiologically (5/8), or histologically after OLTx (3/8). In 1 (5.6%) patient, distant intrahepatic recurrence was found. Out of the 10 (55.6%) patients who did not develop recurrence, 3 underwent OLTx within 1 year after RFA (average 9.3 months).
Differences in patient and tumor characteristics were analyzed between patients who developed LTP (
Based on the
Image analysis protocol. (a) Registration (overlay) of preinterventional and postinterventional CT scans. (b) Semiautomatic delineation of tumor volume. (c) Semiautomatic delineation of RFA volume. (d) Image fusion plane: margin analysis by overlaying pre- and postinterventional imaging. (e) Follow-up scan with local tumor progression.
The average minimal ablative margin in all cases was −6.38 mm (SD: 4.64). The ablative margin size significantly correlated to the occurrence of LTP with a
Boxplot of quantitative ablative margin size for patients with and without local tumor progression (LTP).
Based on the qualitative analysis, 16/18 (88.9%) ablation areas fully encompassed the tumor. Yet, 6 of these patients (42.9%) developed LTP during FU. In 2 (11.1%) patients, the observers concluded that the ablation zone did not completely cover the tumor; these two patients did develop LTP.
One patient developed intrahepatic distant metastatic disease within 18 months after treatment. This was a patient with a fully ablated initial tumor with no LTP.
In this retrospective pilot study, quantitative ablative margin assessment using Mirada RTx software was feasible only in selected patients as in 7 out of 25 patients, the performance of coregistration was insufficient. However, high interobserver agreement rates were found for quantitative assessment in the remaining 18 patients. LTP occurrence correlated with negative margin sizes with
A disadvantage of minimally invasive HCC treatments is that no pathological confirmation of treatment success can be obtained. The chance on treatment success is generally thought to increase when aiming at safety margins of 5 or 10 mm, to overcome potential heat-transduction variations caused by factors such as heat sink, tumor heterogeneity, and liver parenchyma fibrosis or cirrhosis. It is challenging to accurately assess the actual ablative margins. The results of this study indicate that conventional qualitative assessment is prone to overestimation of the obtained ablative margins. Only 2 out of 8 patients who developed LTP were identified qualitatively, whereas all 8 patients were identified using quantitative assessment.
Other studies have addressed the potential of quantitative assessment of ablation margins. A rigid registration algorithm was used in the largest study, by Kim et al. [
As the liver is a deformable organ, a nonrigid registration seems to be a better fit for reliable registration. The Mirada RTx software used in this pilot study is not dedicated for the quantification of ablation margins but has the tools necessary for delineation and nonrigid registration. For future research, the software should be adopted with the purpose to optimize registration of pre- and postablation scans. Adding a step for selecting the liver as volume of interest in which optimal registration should be strived for may increase the registration success for the purpose of ablation margin measurements.
In the quantitative assessment, none of the patients with a fully ablated tumor developed LTP, even in those cases where no safety margin was found. However, tissue shrinks during ablation, which influences the quantification of safety margins [
The LTP rate of 44.4% in this study is comparable to studies with a similar patient population. In a large randomized study that included 701 patients treated with RFA, the HEAT III study, tumor progression rates of 53.3% were found after treatment with RFA in a population with slightly more unfavorable patient and tumor characteristics [
The main limitations of this study are its retrospective design and low sample size. Although the initial cohort consisted of 79 patients, only 25 patients were included, of which 18 patients were assessable for the final analysis. The majority of patients were excluded for this pilot study to prevent potential bias in follow-up data. Secondary exclusion (7/25 included patients) due to unfeasible registration could potentially be reduced by performing a CT scan immediately before and after the ablation. To optimize coregistration of the CT scans, the scan should be acquired with the patient in an identical position and during a similar inhalation mode or with use of high-jet ventilation.
Clinically, LTP is not the most valuable outcome measure. This study was designed as a pilot study to evaluate software that assesses the completeness of a local treatment. Therefore, LTP was chosen as the most relevant parameter for this study rather than survival.
Feasibility of coregistration of pre- and postablation CT images using Mirada RTx software was found for selected patients (18/25), as difference in position and shape of the liver may hamper reliable image coregistration. For patients in whom coregistration is feasible, the interobserver agreement is high, confirming the robustness of this method. Compared to qualitative assessment, quantitative assessment of ablative margins allows better prediction of LTP and may thus be a better method to determine technical success. To increase the feasibility of CT-CT coregistration as a method to determine the endpoint of ablation, there is a need for optimized scanning protocols and dedicated software prospective studies in larger patient cohorts are needed to better determine the risk of recurrence for different ablation margins and to define a cutoff value for the optimal margin.
The data used to support the findings of this study are included within the article.
This research was presented as an oral presentation at Amsterdam Interventional Oncology Symposium (AMIOS 2018).
The authors declare that there are no conflicts of interest regarding the publication of this paper.
Mirada RTx software was provided as in-kind contribution by Mirada Medical Ltd., Oxford, UK.