Minimal ablative margin (MAM) assessment with image fusion: an independent predictor for local tumor progression in hepatocellular carcinoma after stereotactic radiofrequency ablation

This is an institutional review board approved, single-center, retrospective analysis of prospectively collected data from HCC patients referred to stereotactic RFA between January 2009 and February 2016.

In all patients, the treatment plan was established by a multidisciplinary tumor board consisting of hepatologists, oncologists, transplant surgeons, and interventional radiologists. Treatment choice was based on tumor characteristics, Child-Pugh classification, anatomical considerations, and the general patient condition.

Inclusion criteria for stereotactic RFA were as follows: (1) Tumors showed the typical imaging characteristics with hypervascularity in the arterial phase and washout in the delayed portal venous phase on contrast-enhanced CT and were accessible by a percutaneous approach [27]; (2) prothrombin time ratio greater than 50% (prothrombin time with international normalized ratio, G1.7) and platelet count greater than 60,000 cells/mm³; (3) absence of portal vein thrombosis and extrahepatic metastases.

Routine pre-operative evaluation of patients with hepatocellular carcinoma included baseline history, physical examination, and serum laboratory tests. Contrast-enhanced CT of the abdomen was performed for HCC diagnosis accordingly to the European Association for the Study of the Liver (EASL) [27]. In addition, chest CT was routinely performed to exclude the presence of pulmonary metastases. All HCCs included in this study were pathologically confirmed by needle biopsy during the stereotactic RFA procedure.

In total, 146 patients with 273 HCC lesions were identified. Exclusion criteria for retrospective evaluation of MAM were as follows: follow-up < 1 year; extensive liver deformation due to stereotactic RFA of large or multiple tumors leading to an inacceptable fusion result; multiple ablation sessions with incomplete ablation in a single session; multifocal diffuse tumor progression due to very aggressive tumor biology (Fig. 1).

The detailed stereotactic RFA procedure has been described elsewhere [12, 13, 19, 20]. Briefly, the procedure is performed in an interventional CT suite under general anesthesia and neuromuscular blockade. The patient is fixed on a CT table by a vacuum bag (Bluebag, Medical Intelligence). Ten to 15 registration markers for image to patient registration (Beekley Spots, Beekley Corporation) are attached to the skin of the thorax and the upper abdomen. Thereafter, a dual-phase contrast-enhanced planning CT (Siemens SOMATOM Sensation Open, sliding gantry with 82 cm diameter, Siemens AG) with 3-mm slice thickness is acquired. Images are obtained 35–40 and 70–80 s after initiation of contrast material injection (100–150 ml of iopromide [Ultravist 370; Schering AG]), representing late arterial and late portal venous phases. All CT images are acquired with the patient in breath hold by temporary tracheal tube disconnection to overcome differences in position due to respiratory motion.

The CT data is then sent to the optical-based navigation system (Stealth Station Treon Plus, Medtronic Inc.). Multiple electrode positions are planned on the multiplanar and reconstructed images in order to cover the entire tumor volume. Following registration, accuracy check, and sterile draping, the ATLAS aiming device (Medical Intelligence) is manually adjusted using the guidance software of the stereotactic navigation system and 15G coaxial needles (Bard Inc.) are introduced through the aiming device to a pre-planned depth. A CT scan for verification of correct needle placement is obtained. A biopsy sample is taken via the coaxial needles using a 16-gauge core biopsy needle. Subsequently, three radiofrequency probes with a 3 cm active tip (Cool-tip, Medtronic) are introduced via the 15G coaxial needles, the latter being retracted to uncover the active probe exposure. At each position, ablations are performed using the switching control mode for up to three probes during the 16-min ablation per cycle. In case of significant increase of impedance (the so-called roll-off effect) the ablation process was terminated. After ablation completion and removal of RFA probes and co-axial needles by tract cauterization, a dual-phase contrast-enhanced CT scan is obtained for complication and ablation assessment.

A complete ablation was defined by a circumscribed non-enhancing area within and/or extending beyond tumor borders. Any areas of abnormally enhanced tissue in the late arterial phase and washout in the delayed phase that were located within or along the margin of the coagulation zone were considered residual tumor.

Computed tomography imaging fusion was performed using commercially available rigid imaging registration software (Syngo.via VB20A, Siemens Healthineers) with automatic registration followed by verification and, if required, manual registration. The arterial phase was utilized as the image of choice for pre-ablation images as the lesions demarcate clearly from the surrounding liver parenchyma which facilitated an accurate evaluation of the MAM. If possible, the late arterial phase was used as the post-ablation image dataset because the landmarks were clearly identifiable and could be easily correlated with the late arterial planning phase.

At first, images were registered automatically by a rigid registration tool included in the software. However, automatic registration was not satisfactory. Through manual correction by multiplanar slight shifting (translation and rotation) in axial, coronal, and sagittal planes referring to well defined intrahepatic structures, a satisfactory fusion was finally achieved. These so-called intrahepatic landmarks were in most cases vessel bifurcation of hepatic arteries or segmental branches of the portal vein. Landmarks close to the lesion, if possible in the same segment, were preferably used to fuse images accurately. In patients with more than one lesion, image registration was repeated for every lesion in other segments if necessary.

After successful fusion of pre- and post-ablation images, the distances between tumor border and margin of the necrosis zone in the axial, coronal, and sagittal planes were measured. The smallest distance was defined as the minimal ablative margin (MAM). The extension of the minimal ablative margin was described in hours using a 12-h scale of an analogue watch, as illustrated in Fig. 2. An example of successful image fusion and evaluation of MAM is shown in Figs. 3 and 4, while Fig. 5 shows an example of registration failure due to extensive liver deformation.

After stereotactic RFA, contrast-enhanced follow-up CTs with 3-mm slice thickness (including native, late arterial, late portal, and delayed phases) were performed at 3–6-month intervals. For our study, we followed the treated tumors for a maximum time of 36 months for patients without local tumor progression (LTP). In patients with LTP, follow-up ended with the date of detection of the local tumor progression (i.e., event). In patients with liver transplantation after stereotactic RFA as bridging therapy, the histopathological exam of the explanted liver was used to determine LTP. Residual vital tissue was judged as LTP and follow-up ended with the date of liver transplantation (i.e., event).

Local tumor progression was defined as a newly detected nodular hypervascular lesion with washout in the late portal venous phase immediately adjacent to the ablation zone and detected within 36 months after the intervention (Fig. 3e). Newly detected tumors distant to the ablation zone were defined as distant tumor recurrence.

Both image fusion and evaluation of the minimal ablative margin were conducted blinded regarding the oncological outcome of the patient.

Based on previously published data by Nishikawa et al [28], we performed a sample size calculation in order to determine how many lesions had to be included in the present study to detect a possible difference in local tumor progression between ablations with sufficient (> 5 mm) and insufficient minimal margins (< 5 mm). Assuming a type 1 error of 0.05 and a type 2 error of 0.2 (thus yielding 80% statistical power), we found that a total of 77 lesions had to be analyzed to detect such a difference.

The distribution (parametric/non-parametric) of all variables was assessed using histograms. Baseline characteristics of the patients are expressed as mean ± SD or median with interquartile range, as appropriate. Binary logistic regression (LR) was used to identify independent predictors of local tumor progression. In a second step, Cox regression modeling was utilized to visualize the hazard of LTP over time related to different covariates.

Our analysis revealed MAM as the only significant independent predictor of LTP (p = 0.036). The R² (Nagelkerke) of the model was calculated with 0.17, which translates into a strong effect size (0.45) according to Cohen. For each millimeter increase of the MAM, a 30% reduction of the relative risk for LTP was found (OR = 0.7, 95% CI 0.5–0.98, p = 0.036). No other variable such as tumor size or tumor location showed a significant influence on LTP.

The highly significant model of the binary logistic regression with the three possible determinants of LTP is shown in Table 3.

To visualize the probability of LTP over time, Cox regression was utilized. As the MAM was found to be the only predictor of LTP in binary logistic regression, separate lines were coded for lesions with a MAM > 5 mm and < 5 mm, respectively. No LTP was detected in lesions with a MAM > 5 mm. The results are shown in Fig. 6.