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Quantitative Volumetric Assessment of Ablative Margins in Hepatocellular Carcinoma: Predicting Local Tumor Progression Using Nonrigid Registration Software

Quantitative Volumetric Assessment of Ablative Margins in Hepatocellular Carcinoma: Predicting... Hindawi Journal of Oncology Volume 2019, Article ID 4049287, 8 pages https://doi.org/10.1155/2019/4049287 Research Article Quantitative Volumetric Assessment of Ablative Margins in Hepatocellular Carcinoma: Predicting Local Tumor Progression Using Nonrigid Registration Software 1,2 1,2 1 1 P. Hendriks , W. A. Noortman, T. R. Baetens, A. R. van Erkel, 1 1 3 C. S. P. van Rijswijk, R. W. van der Meer, M. J. Coenraad, 1,4 5 1 L. F. de Geus-Oei, C. H. Slump, and M. C. Burgmans Department of Radiology, Leiden University Medical Center, Leiden, Netherlands Technical Medicine, University of Twente, Enschede, Netherlands Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands Biomedical Photonic Imaging Group, TechMed Centre, University of Twente, Enschede, Netherlands Department of Robotics and Mechatronics, University of Twente, Enschede, Netherlands Correspondence should be addressed to P. Hendriks; p.hendriks@lumc.nl Received 25 April 2019; Revised 13 July 2019; Accepted 28 August 2019; Published 19 September 2019 Academic Editor: Roberto Iezzi Copyright © 2019 P. Hendriks et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. After radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC), pre- and postinterventional contrast-enhanced CT (CECT) images are usually qualitatively interpreted to determine technical success, by eyeballing. *e objective of this study was to evaluate the feasibility of quantitative assessment, using a nonrigid CT-CT coregistration algorithm. Materials and Methods. 25 patients treated with RFA for HCC between 2009 and 2014 were retrospectively included. Semiautomated cor- egistration of pre- and posttreatment CECT was performed independently by two radiologists. In scans with a reliable registration, the tumor and ablation area were delineated to identify the side and size of narrowest RFA margin. In addition, qualitative assessment was performed independently by two other radiologists to determine technical success and the anatomical side and size of narrowest margin. Interobserver agreement rates were determined for both methods, and the outcomes were compared with occurrence of local tumor progression (LTP). Results. CT-CT coregistration was technically feasible in 18/25 patients with almost perfect interobserver agreement for quantitative analysis (κ � 0.88). *e interobserver agreement for qualitative RFA margin analysis was κ � 0.64. Using quantitative assessment, negative ablative margins were found in 12/18 patients, with LTP occurring in 8 of these patients. In the remaining 6 patients, quantitative analysis demonstrated complete tumor ablation and no LTP occurred. Conclusion. Feasibility of quantitative RFA margin assessment using nonrigid coregistration of pre- and post- ablation CT is limited, but appears to be a valuable tool in predicting LTP in HCC patients (p � 0.013). stage HCC is now feasible in up to 60% of all new HCC cases 1. Introduction in developed countries [3]. *is makes RFA an increasingly Radiofrequency ablation (RFA) has been recognized as first used treatment modality. Recurrence rates for RFA in very line treatment for very early-stage hepatocellular carcinoma early-stage HCC patients are comparable to those after (HCC) (lesion diameter <2 cm) and is used as treatment for surgical treatment [1]. However, higher recurrence rates are unresectable early-stage HCC (solitary lesion, or a maximum found in patients treated for larger HCC lesions [4–6]. of 3 lesions with a diameter ≤3 cm each), according to the After RFA treatment, two types of intrahepatic re- Barcelona Clinic for Liver Cancer (BCLC) staging system currences may occur. Local tumor progression (LTP) is [1, 2]. As a result of the implementation of surveillance in found in up to 50% of ablations [7] and is known to be high-risk populations, diagnosis of BCLC very early- or early- associated with insufficient ablative margin, large tumor size, 2 Journal of Oncology blood vessels in the direct proximity of the tumor, and March 2014 (n � 79) in our institution were identified ret- adhesion of viable tumor cells to the RFA electrodes [8]. rospectively. *e diagnosis of HCC was based on either Distant intrahepatic recurrence is related more to systemic histology or radiological findings according to European parameters, such as the presence of vascular invasion, Association for the Study of the Liver (EASL) criteria (ar- multifocal disease, elevated alpha-fetoprotein blood levels, terial enhancing lesion>1 cm with washout on the late phase and hepatitis C viral infection [9]. on CT or MRI). Exclusion criteria were multifocal disease *e preferred treatment for early-stage HCC is surgical (n � 27), surgical approach (n � 4), adjuvant trans-arterial resection. However, many patients are not eligible for this chemoembolization (TACE) (n � 7), lateral patient posi- treatment, due to cirrhosis with portal hypertension, un- tioning on the postablation scan (n � 11), and extensive favorable tumor location, and/or comorbidities [1, 10]. *ermal metal artifacts caused by in-vivo RFA probes (n � 5). Finally, ablation is considered as the treatment of choice for unre- 25 patients were included in this study. Baseline charac- sectable early-stage HCC up to 5 cm. Distant intrahepatic re- teristics of this cohort are shown in Table 1. Pre- and currence rates after resection and ablation are similar, but LTP postablation multiphase CECT scans with an arterial and rates are higher after ablation and negatively affect overall portal venous phase were available for all patients. survival [4–6, 11]. To improve the results of RFA in unresectable early-stage HCC, a reduction of LTP rates appears to be crucial. 2.2. RFA Procedure. Percutaneous RFA procedures were Histological confirmation of total tumor necrosis after performed under general anesthesia and with image guid- RFA is not possible. In many centers, the current workflow ance of ultrasound and/or CT. Based on tumor size and involves qualitative assessment of RFA margins by scrolling availability, one of the single electrode RFA systems (3 cm through pre- and postinterventional images, separately. exposed tip Cooltip (Covidien Ltd., Gosport, Hampshire, Technical success is considered when a predefined amount of United Kingdom)) or StarBurst XL (AngioDynamics, energy is successfully delivered to the tumor, and complete Amsterdam, Netherlands)) or multiple electrode RFA sys- tumor coverage with sufficient ablative margins is confirmed tems (3 or 4 cm exposed tip Cooltip with switch control on contrast-enhanced computed tomography (CECT) [8]. In system (Covidien Ltd.)) was used. *e ablation time was set general, an ablative margin of >5 mm, or ideally 10 mm, is 12 minutes for single Cooltip electrode and 16 minutes for recommended [8]. *ese values are rather arbitrarily derived the multiple Cooltip electrodes. Temperature-based ablation from surgical standards and supported by some studies was performed with the StarBurst XL electrode. [10–12]. However, the evidence is limited, and no standardized Immediately after ablation, a CECT scan of the liver was way of ablative margin assessment is currently available. performed on a 16-slice spiral CT (Aquilion-16, Toshiba, Supportive ablation verification software has gained Tokyo, Japan) with the following settings: 120 kV, rotation interest. However, at this moment, software dedicated to 0.5 s, and 16 ×1 mm scanning. Dose weight-dependent quantitative ablation margin assessment is lacking and Ultravist 370 contrast agent or Xenetix 350 contrast agent available software has not been validated in large patient was used with a 15-second and 75-second delay after bolus cohorts. Merging of pre- and postablation scans can be triggering for arterial phase and portal venous phase, re- performed using either nonrigid or rigid coregistration soft- spectively. Consequently, the CECT scans were qualitatively ware. Nonrigid coregistration algorithms allow more degrees of evaluated for technical success. *e ablation was considered freedom in the transformation to fit a scan better onto another. technically successful if the coagulation area fully encom- Besides global linear transformations, like translation and passed the tumor in the absence of residual tumor en- rotation, the algorithm may, e.g., use radial basis functions or hancement. *is assessment was done by visual comparison other free form deformation models that allow for local of the tumor location on preprocedural CT and area of warping of the image to find a better registration. Mirada RTx necrosis on the postprocedural CT (“eyeballing”) and 2D (Mirada Medical Ltd., Oxford, UK) is a software application measurements. developed for radiation therapy treatment planning that uses nonrigid registration of medical image datasets including computed tomography (CT) and magnetic resonance imaging 2.3. Follow-Up. All patients underwent blood tests (in- (MRI). *is software was used in this study. cluding alpha-fetoprotein) and CECT every three months *e primary objective of this study was to assess the after treatment. Upon discretion of the referring physician feasibility of quantitative three-dimensional (3D) margin or interventional radiologist, multiphase MRI was used assessment after nonrigid CT-CT coregistration of pre- and instead of CECT. Liver explants of patients that underwent postinterventional imaging, using Mirada RTx. Secondary an orthotopic liver transplantation (OLTx) were patholog- objectives were to compare quantitative ablative margin ically examined for local tumor progression. *e median assessment with the current workflow of qualitative as- follow-up time was 9.5 months. sessment and to assess whether quantitative assessment allows prediction of local tumor progression. 2.4. Scoring. CT-CT registration and delineation of the tumor volume and RFA ablation volume were performed in 2. Methodology Mirada RTx software. Two radiologists independently per- formed the CT-CT coregistration and delineation of the 2.1. Patients. All patients that were consecutively treated with RFA for de novo HCC between January 2009 and tumor and RFA ablation volume, while being blinded for Journal of Oncology 3 Table 1: Characteristics of analyzed patients. necessarily mean that the tumor was incompletely ablated. *e ablation may have caused tissue shrinkage, and as a result, the ablation area may be smaller than the tumor even Total 25 when the tumor was completely ablated. *e side of LTP Age occurrence was correlated with the side of the minimal Mean (SD) 62, 1 11.8 ablative margin or largest tumor residual. A comparison of Sex patient characteristics between those with and without LTP Male 20 80.0% was performed. Female 5 20.0% Cirrhosis presence Two other radiologists independently repeated the Yes 25 100.0% qualitative assessment of the pre- and postablation scans for No 0 0.0% technical success and determined categorical ablative mar- Ascites presence gins (1: negative, 2: 0 to 5 mm, or 3: ≥5 mm), while being Yes 7 28.0% blinded for follow-up information. Also, the anatomical side No 18 72.0% of narrowest margin was recorded. Interobserver agreement Etiology rates were determined for technical success and margin size. Hepatitis B 2 8.0% In both the quantitative and the qualitative assessment, a Hepatitis C 8 32.0% consensus reevaluation took place by the two radiologists for Alcohol abuse 15 60.0% determining technical success for cases they initially dis- NASH 2 8.0% Cryptogenic 1 4.0% agreed on. ECOG 0 24 96.0% 2.5.Statistics. Interobserver agreement was determined with 1 1 4.0% Child–Pugh score use of unweighted Cohen’s kappa statistics. A κ of 0 meant A 12 48.0% that the agreement was similar to chance, whereas a κ of 1 B 13 52.0% meant perfect agreement [13]. C 0 0.0% Continuous data were analyzed with the independent t- BCLC test and categorical data with the chi-square test. SPSS Very early 10 40.0% version 23.0 was used to perform the data analysis, and a Early 15 60.0% significance interval of 5% was used. Boxplots were created Lesion size (mm) using GraphPad Prism 5 (GraphPad Software, San Diego, Median (range) 20 12–45 California, USA). Year of RFA 2009–2011 10 31.3% 2012–2014 15 46.9% 3. Results NASH � nonalcoholic steatohepatitis; ECOG � Eastern Cooperative Oncol- 3.1. Patients. *e coregistration quality of pre- and post- ogy Group; BCLC � Barcelona Clinic for Liver Cancer; RFA � radiofrequency ablation. More etiological factors could be present in one patient. ablation scans was rated ≤3 in 7/25 (28.0%) patients, who were therefore excluded for further analysis. Table 2 shows all patient and tumor characteristics of the 18 remaining follow-up information. CT-CT coregistration was per- cases that were technically feasible for quantitative analysis. formed using a semiautomated nonrigid registration. Manual alterations were possible by rotation and trans- lation of a scan or with use of a rigid landmark algorithm. 3.2. Scoring. *e interobserver agreement for quantitative *e registration performance was graded on a 5-point scale assessment with use of CT-CTcoregistration and delineation (1 � completely unreliable coregistration; 2 � suboptimal was almost perfect, with a κ of 0.88 (SE: 0.12 and p< 0.01). coregistration; 3 � sufficient quality of coregistration, but Categorical agreement on the minimal margin size (nega- not accurate enough for measurements in mm; 4 � good tive, 0 to 5 mm, or ≥5 mm) was similar with a κ of 0.88 (SE: coregistration; 5 � perfect coregistration). Patients with 0.12 and p< 0.01). A consensus reevaluation of one case led coregistration performances of 1–3 were excluded from to agreement on technical success that the radiologists further analysis. initially disagreed on. A greyscale-based semiautomatic delineation tool was *e interobserver agreement of two radiologists who used with manual adjustments for segmentation of the tu- qualitatively assessed the ablative margins was moderate: 0.64 mor and ablation volume. RFA margins were quantitatively (SE: 0.33 and p< 0.01). Agreement on categorical margin assessed in a fused image window. *e narrowest margin (in assessment was very poor (negative, 0 to 5 mm, or ≥5 mm) mm) as well as the anatomical location of the narrowest with a κ of 0.24 (SE of 0.28 and p � 0.16). Consensus was margin or largest tumor residue was determined. In- reached between the observers on technical success for two terobserver agreement was determined for the categorical cases that they initially disagreed on, for further analysis. 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 3.3. Local Tumor Progression Rate. In 8 out of 18 patients overlay of pre- and postablation CT. *is would not (44.4%), LTP was found, either radiologically (5/8), or 4 Journal of Oncology Table 2: Characteristics of patients technically feasible for quantitative analysis. Total No LTP LTP n n n p value Total 18 10 8 Age Mean (SD) 64.9 (9.0) 66.1 (10.7) 63.4 (6.5) 0.538 Sex Male 14 77.8% 7 70.0% 7 87.5% 0.375 Female 4 22.2% 3 30.0% 1 12.5% Cirrhosis presence Yes 18 100.0% 10 100.0% 8 100.0% No 0 0.0% 0 No 0 0.0% Ascites presence Yes 5 27.8% 3 30.0% 2 25.0% 0.814 No 13 72.2% 7 70.0% 6 75.0% Etiology Hepatitis B 0 0 0 0.800 Hepatitis C 4 2 2 0.410 Alcohol abuse 5 2 3 0.180 NASH 2 2 0 0.250 ECOG 0 17 94.4% 10 100.0% 7 87.5% 0.250 1 1 5.6% 0 No 1 12.5% Child–Pugh score A 9 50.0% 5 50.0% 4 50.0% 1.000 B 9 50.0% 5 50.0% 4 50.0% BCLC Very early 6 33.3% 3 30.0% 3 37.5% 0.737 Early 12 66.7% 7 70.0% 5 62.5% Lesion size Median in mm (range) 22 (12–27) 22 (12–27) 22 (16–25) OLTx <18 months Yes 6 33.3% 3 30.0% 3 37.5% 0.737 No 12 66.7% 7 70.0% 5 62.5% Distant intrahepatic recurrence Yes 1 5.6% 1 10.0% 0 0.0% 0.357 No 17 94.4% 9 90.0% 8 100.0% RFA on target quantitative assessment Yes 6 33.3% 6 60.0% 0 0.0% 0.013 No 12 66.7% 4 40.0% 8 100.0% RFA on target qualitative assessment Yes 16 88.9% 10 100.0% 6 75.0% 0.094 No 2 11.1% 0 2 25.0% Year of RFA 2009–2011 7 38.9% 2 20.0% 5 62.5% 0.066 2012–2014 11 1.6 1% 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. histologically after OLTx (3/8). In 1 (5.6%) patient, distant of these patients, LTP was found. Out of the other 12 pa- intrahepatic recurrence was found. Out of the 10 (55.6%) tients, 8 (66.7%) developed LTP (5 cases of LTP were patients who did not develop recurrence, 3 underwent OLTx identified radiologically, and 3 cases of LTP were patho- within 1 year after RFA (average 9.3 months). logically proven after OLTx). LTP was associated with in- Differences in patient and tumor characteristics were sufficient ablative margins, with a p value of 0.013. All analyzed between patients who developed LTP (n � 8) and patients who developed local tumor progression, did so at patients who did not (n � 10). No significant differences were (one of) the anatomical side(s) with a negative ablative found in patient and tumor characteristics between the margin. An example of the entire workup and occurrence of groups. local recurrence at a negative ablative margin is shown in Based on the quantitative analysis, RFA necrosis fully Figure 1. encompassed the tumor in 6/18 (33.3%) of all patients, with a *e average minimal ablative margin in all cases was mean margin of 0.91 mm (SD: 1.11; range: 0–3 mm). In none − 6.38 mm (SD: 4.64). *e ablative margin size significantly Journal of Oncology 5 (a) (b) (c) (d) (e) Figure 1: 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. 6 Journal of Oncology correlated to the occurrence of LTP with a p value of 0.001. 5mm *e mean ablative margin of patients who developed LTP was − 8.44 mm (SD: 4.27) and − 0.30 mm (SD: 2.00) for patients who did not, as can be seen in Figure 2. Based on the qualitative analysis, 16/18 (88.9%) ablation areas fully encompassed the tumor. Yet, 6 of these patients 0mm (42.9%) developed LTP during FU. In 2 (11.1%) patients, the observers concluded that the ablation zone did not com- pletely cover the tumor; these two patients did develop LTP. One patient developed intrahepatic distant metastatic disease within 18 months after treatment. *is was a patient with a fully ablated initial tumor with no LTP. –5mm 4. Discussion In this retrospective pilot study, quantitative ablative margin assessment using Mirada RTx software was feasible only in –10 mm 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 p � 0.013, indicating a predictive value of quantitative margin assessment. –15 mm A disadvantage of minimally invasive HCC treatments is LTP No LTP that no pathological confirmation of treatment success can Figure 2: Boxplot of quantitative ablative margin size for patients be obtained. *e chance on treatment success is generally with and without local tumor progression (LTP). 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 necessary for delineation and nonrigid registration. For liver parenchyma fibrosis or cirrhosis. It is challenging to future research, the software should be adopted with the accurately assess the actual ablative margins. *e results of purpose to optimize registration of pre- and postablation this study indicate that conventional qualitative assessment scans. Adding a step for selecting the liver as volume of is prone to overestimation of the obtained ablative margins. interest in which optimal registration should be strived for Only 2 out of 8 patients who developed LTP were identified may increase the registration success for the purpose of qualitatively, whereas all 8 patients were identified using ablation margin measurements. In the quantitative assessment, none of the patients with a quantitative assessment. Other studies have addressed the potential of quantitative fully ablated tumor developed LTP, even in those cases where assessment of ablation margins. A rigid registration algorithm no safety margin was found. However, tissue shrinks during was used in the largest study, by Kim et al. [12]. *ey analyzed ablation, which influences the quantification of safety margins 110 HCC tumors and found a cutoff value of >3 mm as a [16–18]. A 0 mm ablative margin on post-RFA imaging may minimal ablation safety margin. Remarkably, in only 3/110 therefore denote a fully ablated tumor with a few millimeter of (2.7%) ablations, the target of 5 mm safety margin was actually margin, as a result of tissue shrinkage. To be fully able to met. Smaller studies used a nonrigid registration algorithm interpret treatment success without pathological confirmation, similar to ours. In a retrospective study in 31 patients with a better understanding of heat conduction and tissue HCC, nonrigid registration of pre- and postablation CT scans shrinkage would be necessary, as the latter seems to occur in an using Hepacare software (Siemens, Germany) was feasible inhomogeneous and unpredictable way [16]. Quantification of ablative margins therefore remains arbitrary, as it may not with an interobserver agreement comparable to our findings [14]. In another small cohort study, correlation between reflect the actual distance between the boundary of the initial margin size and LTP was evaluated in a heterogeneous cohort tumor and the boundary of the ablation area. To use the with different tumor types [15]. In this study, no interobserver software as a decision support tool during ablation procedures, agreement analysis was performed. To our knowledge, the prospective studies in larger patient cohorts are needed to current study has been the first study in which both the determine the risk of recurrence for different ablation margins feasibility of using a nonrigid registration algorithm and the and to set a standard for the optimal ablation margin. correlation between margin size and LTP were reviewed, in a *e LTP rate of 44.4% in this study is comparable to homogeneous HCC population. studies with a similar patient population. In a large ran- domized study that included 701 patients treated with RFA, As the liver is a deformable organ, a nonrigid registration seems to be a better fit for reliable registration. *e Mirada the HEAT III study, tumor progression rates of 53.3% were found after treatment with RFA in a population with slightly RTx software used in this pilot study is not dedicated for the quantification of ablation margins but has the tools more unfavorable patient and tumor characteristics [19]. Journal of Oncology 7 *e main limitations of this study are its retrospective References design and low sample size. Although the initial cohort [1] A. Forner, J. M. Llovet, and J. Bruix, “Hepatocellular carci- consisted of 79 patients, only 25 patients were included, of noma,” 6e Lancet, vol. 379, no. 9822, pp. 1245–1255, 2012. which 18 patients were assessable for the final analysis. *e [2] T. Livraghi, F. Meloni, M. 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Quantitative Volumetric Assessment of Ablative Margins in Hepatocellular Carcinoma: Predicting Local Tumor Progression Using Nonrigid Registration Software

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Hindawi Publishing Corporation
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Copyright © 2019 P. Hendriks et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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1687-8450
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1687-8469
DOI
10.1155/2019/4049287
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Hindawi Journal of Oncology Volume 2019, Article ID 4049287, 8 pages https://doi.org/10.1155/2019/4049287 Research Article Quantitative Volumetric Assessment of Ablative Margins in Hepatocellular Carcinoma: Predicting Local Tumor Progression Using Nonrigid Registration Software 1,2 1,2 1 1 P. Hendriks , W. A. Noortman, T. R. Baetens, A. R. van Erkel, 1 1 3 C. S. P. van Rijswijk, R. W. van der Meer, M. J. Coenraad, 1,4 5 1 L. F. de Geus-Oei, C. H. Slump, and M. C. Burgmans Department of Radiology, Leiden University Medical Center, Leiden, Netherlands Technical Medicine, University of Twente, Enschede, Netherlands Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, Netherlands Biomedical Photonic Imaging Group, TechMed Centre, University of Twente, Enschede, Netherlands Department of Robotics and Mechatronics, University of Twente, Enschede, Netherlands Correspondence should be addressed to P. Hendriks; p.hendriks@lumc.nl Received 25 April 2019; Revised 13 July 2019; Accepted 28 August 2019; Published 19 September 2019 Academic Editor: Roberto Iezzi Copyright © 2019 P. Hendriks et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. After radiofrequency ablation (RFA) of hepatocellular carcinoma (HCC), pre- and postinterventional contrast-enhanced CT (CECT) images are usually qualitatively interpreted to determine technical success, by eyeballing. *e objective of this study was to evaluate the feasibility of quantitative assessment, using a nonrigid CT-CT coregistration algorithm. Materials and Methods. 25 patients treated with RFA for HCC between 2009 and 2014 were retrospectively included. Semiautomated cor- egistration of pre- and posttreatment CECT was performed independently by two radiologists. In scans with a reliable registration, the tumor and ablation area were delineated to identify the side and size of narrowest RFA margin. In addition, qualitative assessment was performed independently by two other radiologists to determine technical success and the anatomical side and size of narrowest margin. Interobserver agreement rates were determined for both methods, and the outcomes were compared with occurrence of local tumor progression (LTP). Results. CT-CT coregistration was technically feasible in 18/25 patients with almost perfect interobserver agreement for quantitative analysis (κ � 0.88). *e interobserver agreement for qualitative RFA margin analysis was κ � 0.64. Using quantitative assessment, negative ablative margins were found in 12/18 patients, with LTP occurring in 8 of these patients. In the remaining 6 patients, quantitative analysis demonstrated complete tumor ablation and no LTP occurred. Conclusion. Feasibility of quantitative RFA margin assessment using nonrigid coregistration of pre- and post- ablation CT is limited, but appears to be a valuable tool in predicting LTP in HCC patients (p � 0.013). stage HCC is now feasible in up to 60% of all new HCC cases 1. Introduction in developed countries [3]. *is makes RFA an increasingly Radiofrequency ablation (RFA) has been recognized as first used treatment modality. Recurrence rates for RFA in very line treatment for very early-stage hepatocellular carcinoma early-stage HCC patients are comparable to those after (HCC) (lesion diameter <2 cm) and is used as treatment for surgical treatment [1]. However, higher recurrence rates are unresectable early-stage HCC (solitary lesion, or a maximum found in patients treated for larger HCC lesions [4–6]. of 3 lesions with a diameter ≤3 cm each), according to the After RFA treatment, two types of intrahepatic re- Barcelona Clinic for Liver Cancer (BCLC) staging system currences may occur. Local tumor progression (LTP) is [1, 2]. As a result of the implementation of surveillance in found in up to 50% of ablations [7] and is known to be high-risk populations, diagnosis of BCLC very early- or early- associated with insufficient ablative margin, large tumor size, 2 Journal of Oncology blood vessels in the direct proximity of the tumor, and March 2014 (n � 79) in our institution were identified ret- adhesion of viable tumor cells to the RFA electrodes [8]. rospectively. *e diagnosis of HCC was based on either Distant intrahepatic recurrence is related more to systemic histology or radiological findings according to European parameters, such as the presence of vascular invasion, Association for the Study of the Liver (EASL) criteria (ar- multifocal disease, elevated alpha-fetoprotein blood levels, terial enhancing lesion>1 cm with washout on the late phase and hepatitis C viral infection [9]. on CT or MRI). Exclusion criteria were multifocal disease *e preferred treatment for early-stage HCC is surgical (n � 27), surgical approach (n � 4), adjuvant trans-arterial resection. However, many patients are not eligible for this chemoembolization (TACE) (n � 7), lateral patient posi- treatment, due to cirrhosis with portal hypertension, un- tioning on the postablation scan (n � 11), and extensive favorable tumor location, and/or comorbidities [1, 10]. *ermal metal artifacts caused by in-vivo RFA probes (n � 5). Finally, ablation is considered as the treatment of choice for unre- 25 patients were included in this study. Baseline charac- sectable early-stage HCC up to 5 cm. Distant intrahepatic re- teristics of this cohort are shown in Table 1. Pre- and currence rates after resection and ablation are similar, but LTP postablation multiphase CECT scans with an arterial and rates are higher after ablation and negatively affect overall portal venous phase were available for all patients. survival [4–6, 11]. To improve the results of RFA in unresectable early-stage HCC, a reduction of LTP rates appears to be crucial. 2.2. RFA Procedure. Percutaneous RFA procedures were Histological confirmation of total tumor necrosis after performed under general anesthesia and with image guid- RFA is not possible. In many centers, the current workflow ance of ultrasound and/or CT. Based on tumor size and involves qualitative assessment of RFA margins by scrolling availability, one of the single electrode RFA systems (3 cm through pre- and postinterventional images, separately. exposed tip Cooltip (Covidien Ltd., Gosport, Hampshire, Technical success is considered when a predefined amount of United Kingdom)) or StarBurst XL (AngioDynamics, energy is successfully delivered to the tumor, and complete Amsterdam, Netherlands)) or multiple electrode RFA sys- tumor coverage with sufficient ablative margins is confirmed tems (3 or 4 cm exposed tip Cooltip with switch control on contrast-enhanced computed tomography (CECT) [8]. In system (Covidien Ltd.)) was used. *e ablation time was set general, an ablative margin of >5 mm, or ideally 10 mm, is 12 minutes for single Cooltip electrode and 16 minutes for recommended [8]. *ese values are rather arbitrarily derived the multiple Cooltip electrodes. Temperature-based ablation from surgical standards and supported by some studies was performed with the StarBurst XL electrode. [10–12]. However, the evidence is limited, and no standardized Immediately after ablation, a CECT scan of the liver was way of ablative margin assessment is currently available. performed on a 16-slice spiral CT (Aquilion-16, Toshiba, Supportive ablation verification software has gained Tokyo, Japan) with the following settings: 120 kV, rotation interest. However, at this moment, software dedicated to 0.5 s, and 16 ×1 mm scanning. Dose weight-dependent quantitative ablation margin assessment is lacking and Ultravist 370 contrast agent or Xenetix 350 contrast agent available software has not been validated in large patient was used with a 15-second and 75-second delay after bolus cohorts. Merging of pre- and postablation scans can be triggering for arterial phase and portal venous phase, re- performed using either nonrigid or rigid coregistration soft- spectively. Consequently, the CECT scans were qualitatively ware. Nonrigid coregistration algorithms allow more degrees of evaluated for technical success. *e ablation was considered freedom in the transformation to fit a scan better onto another. technically successful if the coagulation area fully encom- Besides global linear transformations, like translation and passed the tumor in the absence of residual tumor en- rotation, the algorithm may, e.g., use radial basis functions or hancement. *is assessment was done by visual comparison other free form deformation models that allow for local of the tumor location on preprocedural CT and area of warping of the image to find a better registration. Mirada RTx necrosis on the postprocedural CT (“eyeballing”) and 2D (Mirada Medical Ltd., Oxford, UK) is a software application measurements. developed for radiation therapy treatment planning that uses nonrigid registration of medical image datasets including computed tomography (CT) and magnetic resonance imaging 2.3. Follow-Up. All patients underwent blood tests (in- (MRI). *is software was used in this study. cluding alpha-fetoprotein) and CECT every three months *e primary objective of this study was to assess the after treatment. Upon discretion of the referring physician feasibility of quantitative three-dimensional (3D) margin or interventional radiologist, multiphase MRI was used assessment after nonrigid CT-CT coregistration of pre- and instead of CECT. Liver explants of patients that underwent postinterventional imaging, using Mirada RTx. Secondary an orthotopic liver transplantation (OLTx) were patholog- objectives were to compare quantitative ablative margin ically examined for local tumor progression. *e median assessment with the current workflow of qualitative as- follow-up time was 9.5 months. sessment and to assess whether quantitative assessment allows prediction of local tumor progression. 2.4. Scoring. CT-CT registration and delineation of the tumor volume and RFA ablation volume were performed in 2. Methodology Mirada RTx software. Two radiologists independently per- formed the CT-CT coregistration and delineation of the 2.1. Patients. All patients that were consecutively treated with RFA for de novo HCC between January 2009 and tumor and RFA ablation volume, while being blinded for Journal of Oncology 3 Table 1: Characteristics of analyzed patients. necessarily mean that the tumor was incompletely ablated. *e ablation may have caused tissue shrinkage, and as a result, the ablation area may be smaller than the tumor even Total 25 when the tumor was completely ablated. *e side of LTP Age occurrence was correlated with the side of the minimal Mean (SD) 62, 1 11.8 ablative margin or largest tumor residual. A comparison of Sex patient characteristics between those with and without LTP Male 20 80.0% was performed. Female 5 20.0% Cirrhosis presence Two other radiologists independently repeated the Yes 25 100.0% qualitative assessment of the pre- and postablation scans for No 0 0.0% technical success and determined categorical ablative mar- Ascites presence gins (1: negative, 2: 0 to 5 mm, or 3: ≥5 mm), while being Yes 7 28.0% blinded for follow-up information. Also, the anatomical side No 18 72.0% of narrowest margin was recorded. Interobserver agreement Etiology rates were determined for technical success and margin size. Hepatitis B 2 8.0% In both the quantitative and the qualitative assessment, a Hepatitis C 8 32.0% consensus reevaluation took place by the two radiologists for Alcohol abuse 15 60.0% determining technical success for cases they initially dis- NASH 2 8.0% Cryptogenic 1 4.0% agreed on. ECOG 0 24 96.0% 2.5.Statistics. Interobserver agreement was determined with 1 1 4.0% Child–Pugh score use of unweighted Cohen’s kappa statistics. A κ of 0 meant A 12 48.0% that the agreement was similar to chance, whereas a κ of 1 B 13 52.0% meant perfect agreement [13]. C 0 0.0% Continuous data were analyzed with the independent t- BCLC test and categorical data with the chi-square test. SPSS Very early 10 40.0% version 23.0 was used to perform the data analysis, and a Early 15 60.0% significance interval of 5% was used. Boxplots were created Lesion size (mm) using GraphPad Prism 5 (GraphPad Software, San Diego, Median (range) 20 12–45 California, USA). Year of RFA 2009–2011 10 31.3% 2012–2014 15 46.9% 3. Results NASH � nonalcoholic steatohepatitis; ECOG � Eastern Cooperative Oncol- 3.1. Patients. *e coregistration quality of pre- and post- ogy Group; BCLC � Barcelona Clinic for Liver Cancer; RFA � radiofrequency ablation. More etiological factors could be present in one patient. ablation scans was rated ≤3 in 7/25 (28.0%) patients, who were therefore excluded for further analysis. Table 2 shows all patient and tumor characteristics of the 18 remaining follow-up information. CT-CT coregistration was per- cases that were technically feasible for quantitative analysis. formed using a semiautomated nonrigid registration. Manual alterations were possible by rotation and trans- lation of a scan or with use of a rigid landmark algorithm. 3.2. Scoring. *e interobserver agreement for quantitative *e registration performance was graded on a 5-point scale assessment with use of CT-CTcoregistration and delineation (1 � completely unreliable coregistration; 2 � suboptimal was almost perfect, with a κ of 0.88 (SE: 0.12 and p< 0.01). coregistration; 3 � sufficient quality of coregistration, but Categorical agreement on the minimal margin size (nega- not accurate enough for measurements in mm; 4 � good tive, 0 to 5 mm, or ≥5 mm) was similar with a κ of 0.88 (SE: coregistration; 5 � perfect coregistration). Patients with 0.12 and p< 0.01). A consensus reevaluation of one case led coregistration performances of 1–3 were excluded from to agreement on technical success that the radiologists further analysis. initially disagreed on. A greyscale-based semiautomatic delineation tool was *e interobserver agreement of two radiologists who used with manual adjustments for segmentation of the tu- qualitatively assessed the ablative margins was moderate: 0.64 mor and ablation volume. RFA margins were quantitatively (SE: 0.33 and p< 0.01). Agreement on categorical margin assessed in a fused image window. *e narrowest margin (in assessment was very poor (negative, 0 to 5 mm, or ≥5 mm) mm) as well as the anatomical location of the narrowest with a κ of 0.24 (SE of 0.28 and p � 0.16). Consensus was margin or largest tumor residue was determined. In- reached between the observers on technical success for two terobserver agreement was determined for the categorical cases that they initially disagreed on, for further analysis. 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 3.3. Local Tumor Progression Rate. In 8 out of 18 patients overlay of pre- and postablation CT. *is would not (44.4%), LTP was found, either radiologically (5/8), or 4 Journal of Oncology Table 2: Characteristics of patients technically feasible for quantitative analysis. Total No LTP LTP n n n p value Total 18 10 8 Age Mean (SD) 64.9 (9.0) 66.1 (10.7) 63.4 (6.5) 0.538 Sex Male 14 77.8% 7 70.0% 7 87.5% 0.375 Female 4 22.2% 3 30.0% 1 12.5% Cirrhosis presence Yes 18 100.0% 10 100.0% 8 100.0% No 0 0.0% 0 No 0 0.0% Ascites presence Yes 5 27.8% 3 30.0% 2 25.0% 0.814 No 13 72.2% 7 70.0% 6 75.0% Etiology Hepatitis B 0 0 0 0.800 Hepatitis C 4 2 2 0.410 Alcohol abuse 5 2 3 0.180 NASH 2 2 0 0.250 ECOG 0 17 94.4% 10 100.0% 7 87.5% 0.250 1 1 5.6% 0 No 1 12.5% Child–Pugh score A 9 50.0% 5 50.0% 4 50.0% 1.000 B 9 50.0% 5 50.0% 4 50.0% BCLC Very early 6 33.3% 3 30.0% 3 37.5% 0.737 Early 12 66.7% 7 70.0% 5 62.5% Lesion size Median in mm (range) 22 (12–27) 22 (12–27) 22 (16–25) OLTx <18 months Yes 6 33.3% 3 30.0% 3 37.5% 0.737 No 12 66.7% 7 70.0% 5 62.5% Distant intrahepatic recurrence Yes 1 5.6% 1 10.0% 0 0.0% 0.357 No 17 94.4% 9 90.0% 8 100.0% RFA on target quantitative assessment Yes 6 33.3% 6 60.0% 0 0.0% 0.013 No 12 66.7% 4 40.0% 8 100.0% RFA on target qualitative assessment Yes 16 88.9% 10 100.0% 6 75.0% 0.094 No 2 11.1% 0 2 25.0% Year of RFA 2009–2011 7 38.9% 2 20.0% 5 62.5% 0.066 2012–2014 11 1.6 1% 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. histologically after OLTx (3/8). In 1 (5.6%) patient, distant of these patients, LTP was found. Out of the other 12 pa- intrahepatic recurrence was found. Out of the 10 (55.6%) tients, 8 (66.7%) developed LTP (5 cases of LTP were patients who did not develop recurrence, 3 underwent OLTx identified radiologically, and 3 cases of LTP were patho- within 1 year after RFA (average 9.3 months). logically proven after OLTx). LTP was associated with in- Differences in patient and tumor characteristics were sufficient ablative margins, with a p value of 0.013. All analyzed between patients who developed LTP (n � 8) and patients who developed local tumor progression, did so at patients who did not (n � 10). No significant differences were (one of) the anatomical side(s) with a negative ablative found in patient and tumor characteristics between the margin. An example of the entire workup and occurrence of groups. local recurrence at a negative ablative margin is shown in Based on the quantitative analysis, RFA necrosis fully Figure 1. encompassed the tumor in 6/18 (33.3%) of all patients, with a *e average minimal ablative margin in all cases was mean margin of 0.91 mm (SD: 1.11; range: 0–3 mm). In none − 6.38 mm (SD: 4.64). *e ablative margin size significantly Journal of Oncology 5 (a) (b) (c) (d) (e) Figure 1: 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. 6 Journal of Oncology correlated to the occurrence of LTP with a p value of 0.001. 5mm *e mean ablative margin of patients who developed LTP was − 8.44 mm (SD: 4.27) and − 0.30 mm (SD: 2.00) for patients who did not, as can be seen in Figure 2. Based on the qualitative analysis, 16/18 (88.9%) ablation areas fully encompassed the tumor. Yet, 6 of these patients 0mm (42.9%) developed LTP during FU. In 2 (11.1%) patients, the observers concluded that the ablation zone did not com- pletely cover the tumor; these two patients did develop LTP. One patient developed intrahepatic distant metastatic disease within 18 months after treatment. *is was a patient with a fully ablated initial tumor with no LTP. –5mm 4. Discussion In this retrospective pilot study, quantitative ablative margin assessment using Mirada RTx software was feasible only in –10 mm 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 p � 0.013, indicating a predictive value of quantitative margin assessment. –15 mm A disadvantage of minimally invasive HCC treatments is LTP No LTP that no pathological confirmation of treatment success can Figure 2: Boxplot of quantitative ablative margin size for patients be obtained. *e chance on treatment success is generally with and without local tumor progression (LTP). 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 necessary for delineation and nonrigid registration. For liver parenchyma fibrosis or cirrhosis. It is challenging to future research, the software should be adopted with the accurately assess the actual ablative margins. *e results of purpose to optimize registration of pre- and postablation this study indicate that conventional qualitative assessment scans. Adding a step for selecting the liver as volume of is prone to overestimation of the obtained ablative margins. interest in which optimal registration should be strived for Only 2 out of 8 patients who developed LTP were identified may increase the registration success for the purpose of qualitatively, whereas all 8 patients were identified using ablation margin measurements. In the quantitative assessment, none of the patients with a quantitative assessment. Other studies have addressed the potential of quantitative fully ablated tumor developed LTP, even in those cases where assessment of ablation margins. A rigid registration algorithm no safety margin was found. However, tissue shrinks during was used in the largest study, by Kim et al. [12]. *ey analyzed ablation, which influences the quantification of safety margins 110 HCC tumors and found a cutoff value of >3 mm as a [16–18]. A 0 mm ablative margin on post-RFA imaging may minimal ablation safety margin. Remarkably, in only 3/110 therefore denote a fully ablated tumor with a few millimeter of (2.7%) ablations, the target of 5 mm safety margin was actually margin, as a result of tissue shrinkage. To be fully able to met. Smaller studies used a nonrigid registration algorithm interpret treatment success without pathological confirmation, similar to ours. In a retrospective study in 31 patients with a better understanding of heat conduction and tissue HCC, nonrigid registration of pre- and postablation CT scans shrinkage would be necessary, as the latter seems to occur in an using Hepacare software (Siemens, Germany) was feasible inhomogeneous and unpredictable way [16]. Quantification of ablative margins therefore remains arbitrary, as it may not with an interobserver agreement comparable to our findings [14]. In another small cohort study, correlation between reflect the actual distance between the boundary of the initial margin size and LTP was evaluated in a heterogeneous cohort tumor and the boundary of the ablation area. To use the with different tumor types [15]. In this study, no interobserver software as a decision support tool during ablation procedures, agreement analysis was performed. To our knowledge, the prospective studies in larger patient cohorts are needed to current study has been the first study in which both the determine the risk of recurrence for different ablation margins feasibility of using a nonrigid registration algorithm and the and to set a standard for the optimal ablation margin. correlation between margin size and LTP were reviewed, in a *e LTP rate of 44.4% in this study is comparable to homogeneous HCC population. studies with a similar patient population. In a large ran- domized study that included 701 patients treated with RFA, As the liver is a deformable organ, a nonrigid registration seems to be a better fit for reliable registration. *e Mirada the HEAT III study, tumor progression rates of 53.3% were found after treatment with RFA in a population with slightly RTx software used in this pilot study is not dedicated for the quantification of ablation margins but has the tools more unfavorable patient and tumor characteristics [19]. Journal of Oncology 7 *e main limitations of this study are its retrospective References design and low sample size. Although the initial cohort [1] A. Forner, J. M. Llovet, and J. Bruix, “Hepatocellular carci- consisted of 79 patients, only 25 patients were included, of noma,” 6e Lancet, vol. 379, no. 9822, pp. 1245–1255, 2012. which 18 patients were assessable for the final analysis. *e [2] T. Livraghi, F. Meloni, M. 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