Contrast enhanced ultrasound (CEUS) with parametric imaging after irreversible electroporation (IRE) of the prostate to assess the success of prostate cancer treatment

1 Introduction

Prostate cancer is the second most frequently diagnosed cancer in men worldwide [1]. Without distant metastases, the chances of curing prostate cancer are high. Radical prostatectomy is associated with postoperative risk factors like erectile dysfunction and incontinence [2]. Other treatment options such as radiation and thermal ablation also mostly destroy the function of the gland [3]. Consequently, there is the wish of alternative treatment strategies, especially for smaller tumor areas, but also the need of fast and reliable diagnosis also during follow-up [4–6].

Contrast enhanced ultrasound (CEUS) is used to display micro-vascularization in prostate cancer dynamically using second generation ultrasound contrast agents and contrast harmonic imaging (CHI). While prostate ultrasound is routinely performed by 3D technique and the use of an endorectal probe, transabdominal 3D ultrasound represents an easier and more convenient examination procedure; hence compliance in patients for follow-up is higher. By using strictly intravascular sulfur hexafluoride microbubbles (SonoVue®, Bracco, Milan, Italy), the tumor vascularization can be depicted by real time imaging. Typically, tumors show a nodular contrast enhancement at the margins, but without the typical wash-out in the late phase, that is seen in metastases and HCC for example [7]. The quantification of microcirculation can be performed with (integrated) perfusion software and parametric imaging with pseudo-colors. Integrated software means, there is no data transfer necessary for the perfusion analysis. The perfusion analysis can be performed on the ultrasound machine itself. The results of the analysis can be stored in PACS as well. Pseudo-colors, also known as false colors are used for information visualization. In this case those colors were defined, that red shows a high enhancement, yellow and orange moderate enhancement, whereas blue and green as well as purple show reduced enhancement.

In well-selected cases with circumscribed prostate cancer without distant metastases and without infiltration of the capsule an irreversible electroporation (IRE) can be performed [8–10]. IRE is a non-thermal ablation method used to destroy homeostasis of the cell membrane [11]. IRE can either be performed with ultrasound guidance or with CT fluoroscopy guidance. IRE is a safe technique for ablation [12]. Usually there are reactive changes following the ablation in terms of a prostatitis. Only in very few cases there might be a severe bleeding, an infection, abscesses or fistulas. The microcirculation is reduced after IRE [13], however the macro-circulation can remain normal.

The aim of this study was to assess the success of IRE in patients with prostate cancer and to differentiate between reactive changes and residual tumor

2 Material and methods

Patients included in this study had histopathologically proven prostate cancer, without distant metastases and have not yet received any other treatment for prostate cancer. The biopsies were performed 3 months prior to the treatment and (chronic) prostatitis was excluded. This is a retrospective analysis of 50 patients after IRE in prostate cancer between 50–79 years (mean 65 years). All patients had a Gleason Score < 6 (mostly 3 + 3 which means well-differentiated, low aggressive tumors). None of the patients has received any previous treatment for prostate cancer. This study was waived by the local ethical board (17-789-104). Written informed consent was obtained in all cases.

Before and within 24 hours after the IRE, each patient received a transabdominal sonography using a C1-6 MHz convex matrix probe with 3D option by the cross beam technology and a three plane evaluation after sweep scanning (LOGIQ E9, GE Healthcare, Solingen, Germany). The macro-vascularization was documented using Power Doppler and color-coded Doppler sonography (CCDS). Besides the vascularization in the periprostatic space and the vascularization of the kidneys were also documented to exclude problems with the macro-vascularization or urinary retention after IRE. Free fluid, hematoma and abscesses were to be excluded by performing a standardized abdominal scan. The follow-up scans up to 6 months after the treatment were conducted with the same US protocol.

Following the grey scale examination, CEUS was performed after i.v. bolus injection of 2.0–2.4 ml contrast agent (SonoVue®, Bracco, Milan, Italy) via a cubital vein, followed by a 10 ml saline flush. The standard presets for CEUS with contrast harmonic imaging (CHI) and low mechanical index (MI < 0.2) were used. Digital DICOM loops were continuously stored for one minute in PACS (picture archiving and communication system). The microcirculation was documented in sweep technology from the apical to the basal and from the ventral to the dorsal areas of the prostate. For the arterial phase short loops were continuously stored for one minute and afterwards single images were stored up to the late phase (three minutes after contrast injection). Furthermore, the kidneys were scanned in the late phase to exclude perfusion defects.

For the parametric evaluation, the already stored DICOM loops were independently evaluated using integrated perfusion software. Pseudo-colors and perfusion imaging were evaluated in the wash-in phase between 10–40 seconds after the injection. Red shades show hyperperfusion, and orange slight hyperperfusion. Whereas purple shows reduced perfusion. The loops and parametric images were read by two experienced radiologists in consensus.

Additionally to CEUS, standardized follow-up imaging consists of multiparametric MRI (mpMRI) with or without contrast media (according to the renal function) for primary diagnostics and six months after ablation using a 3T MRI (Skyra, Siemens, Erlangen Germany) and a body phase-array coil. We performed T2 sequences in axial (Fig. 1), sagittal and coronal planes, diffusion weighted imaging (DWI) with the corresponding ADC map, which was automatically calculated from all three b-values. Furthermore, dynamic T1 VIBE contrast-enhanced sequences were acquired. As contrast media we used 6–8 ml of Gadovist® (1,0 mmol/ml, Bayer Vital GmbH, Leverkusen, Germany) according to the body weight. Local lymph node metastases (i.e. enlarged and round lymph nodes), as well as suspicious areas and extracapsular growth were excluded in follow-up scans. Patients with lymph node metastases or extracapsular growth at primary diagnostics were excluded from the study because they did not qualify for IRE.

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Fig. 1

Axial T2w MRI of the prostate. In the left peripheral zone there is a hypointense area that has been proven to be prostate cancer (left image). After the ablation the left hemisphere of the prostate is swollen and the tumor is completely covered within the ablation zone (right), catheter in place. No infiltration of the surrounding tissue is seen, no free fluid.

IRE is a non-thermal alternative to radiofrequency ablation (RFA) and microwave ablation (MWA). 2–6 IRE electrodes are placed parallel in and around the tumor area to deliver electrical pulses. Cell death is caused by destroying the homeostasis of the cell membrane. In contrast to thermal methods like microwave ablation (MWA) or radiofrequency ablation (RFA), IRE protects heat-sensitive structures e.g. nerves, in these cases the paraprostatic plexus. Even tumors that are close to the major vessels of an organ can be treated with IRE. An experienced interventional radiologist performed all ablations using the NanoKnife® System (AngioDynamics, Latham, NY, USA). All patients received general anesthesia for the treatment. Since IRE is not yet recommended in the guidelines for treatment of prostate cancer, the different treatment options were discussed with the patient beforehand in urology. If the patient decided to undergo IRE the patients were then referred to our hospital for the treatment.

For statistical analysis IBM SPSS Statistics for Windows Version 25.0 (Armonk, NY: IBM Corp) was used.

In our study the tumor size ranged between 0.5 and 1.5 cm. Sufficient image quality for dynamic transabominal CEUS was obtained in all cases. Parametric imaging was calculated in all patients using integrated perfusion software. No contrast media intolerances were noted. As major complication one patient suffered from a fistula to the rectum due to IRE and had to undergo a rectectomy. Bleeding within the ablation was not counted as complication, as this is often observed after IRE. No bleeding outside the prostate was observed, no urinary retention of the kidneys occurred. No contrast media intolerances were noted.

Out of the 50 patients 37 men were successfully treated with IRE for prostate cancer, meaning no local recurrence 6 months after the ablation. In all these cases no tumor suspicious nodular enhancement was found in parametric imaging. Post-interventionally, more spacious marginal hyperenhancement was more likely to be associated with prostatitis (18 cases).

13 patients showed recurrence after the ablation. Prostate cancer and its recurrence is characterized by dynamic early nodular hypervascularisation with fast and high wash-in. In the late venous phase after 1 min, no wash-out was observed. Parametric imaging with pseudo colors shows corresponding nodular red and yellow shades (Fig. 2). In contrast, cases of prostatitis showed spacious hypervascularization without any nodular enhancement (Fig. 3). In all patients the microcirculation of the prostate clearly decreased, whereas the macro-circulation remained unaffected (Fig. 4).

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Fig. 2

Transabdominal sonography with 1–6 MHz convex probe after i.v. injection of 2.0 ml SonoVue ®. On the right there is the original CEUS image with a nodular early hypervascularization. On the left there is the calculated parametric imaging with also a nodular hyper enhancement (arrow, corresponding red shades).

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Fig. 3

Transabdominal sonography with 1–6 MHz convex probe after i.v. injection of 2.0 ml SonoVue ®. On the left grey-scale image, on the right calculated parametric imaging. These images show a representative case of prostatitis, where spacious hypervascularization is seen. There is no nodular hypervascularization.

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Fig. 4

Transabdominal sonography with 1–6 MHz convex probe after i.v. injection of 2.0 ml SonoVue ®, only the parametric imaging is shown. Case of histopathologically proven prostate cancer (on the left) before the treatment with IRE. On the right side, same patient after the treatment of his prostate cancer. The macro-vascularization is still seen, whereas the microcirculation has decreased.

The sensitivity for detecting residual tumor with CEUS compared to MRI was 76%, the specificity was 81%. The corresponding positive predictive value (PPV) was 73% and de negative predictive value (NPV) was 83%.

All patients with recurrence were correctly identified with CEUS and parametric imaging. Those patients were consecutively retreated with either IRE or radical prostatectomy.

IRE is not yet fully recommended in the guidelines for prostate cancer treatment and so far is mostly performed in the setting of clinical studies [8, 14]. IRE is performed to cause cell death, but in contrast to the thermal ablation methods (RFA and MWA), it spares the nerval plexus and important macro-vascular structures. This is also the difficulty of post-interventional imaging. Right after IRE there might be bleeding in the ablation area, reactive changes like prostatitis or in case of devascularization of the larger vessels there might be necrosis [15]. Therefore, the post-interventional control is used to exclude these complications, e.g. abscesses, urinary retention and possible fistulas. A successfully treated area should be mostly devascularized. The sonographic examination allows to judge the local post-ablation status as well as for additional abdominal assessment. This study examines the value of trans-abdominal imaging in terms of assessment of IRE for follow-up using parametric perfusion imaging with pseudo colors. The value of transrectal CEUS for detection and classification of prostate cancer with the help of perfusion imaging has already been shown [16] and also the decrease of microcirculation can be observed right after the treatment [13, 18]. However, it is important to mention, that with the use of transabdominal probes the examination and the presumed compliance of patients in the follow-up is higher than with transrectal probes. Own studies have already shown, that the use of perfusion analysis and pseudo-colors are a reliable tool to distinguish between reactive changes and remaining tumor areas after ablation treatment of malignant liver lesions [19, 20].

The results of perfusion parametric imaging point out that a hyperemia in prostatitis is shown as spacious red and yellow shades and a remaining tumor as circumscribed red area. An ablation defect is displayed as a green and dark purple area. The remaining tumor shows an early arterial enhancement and the contrast media behavior is similar to the surrounding tissue. However, in contrast to malignant liver lesions, there is no clear wash out in the late phase. Furthermore, it has already been proven, that CEUS and MRI are both capable of assessing the ablation defect correctly [21].

Studies of our own working group in the detection of prostate cancer with color-coded perfusion software show that especially tumors with a high Gleason score can be detected [18]. However, it might still be difficult to differentiate between tumor and reactive changes, if there is no distinctive irregular contrast-media enhancement, like in tumors with low Gleason score and low perfusion. Other studies with endorectal probes and focused biopsies have already proven that there is a complete devascularization in the areas of successful IRE [22]. Is has already been shown that the success of prostate arterial embolization (PAE) in benign prostate hyperplasia can be assessed with CEUS and perfusion imaging [23].

The contrast-media for MRI contains gadolinium with all the known side effects, whereas SonoVue® as contrast media used for CEUS is safe, even in patients with impaired renal function and hyperthyreoidism [24]. Using CEUS a maximum 2.0 ml of contrast media as bolus and a special matrix probe (1–6 MHz) the dynamic microcirculation can be assessed during transabdominal examination. However, ultrasound contrast media is not tumor specific and only after dynamic perfusion imaging signs of remaining tumor and reactive changes are shown after IRE [25]. Additionally, compared to MRI, CEUS is more cost-effective [26]. Using a fusion technique of MRI and ultrasound, biopsies of the prostate are most effective [27]. The preceding biopsies however do not affect the perfusion of the prostate, since there is no difference in micro-circulation, and scars will not show hyper-perfusion.

With the use of high-end ultrasound machines the prostate can be displayed using a transabdominal probe, which is more convenient for the patient and therefore presumably increases compliance in the follow-up care.

5 Conclusion

Transabdominal CEUS and parametric imaging enable a critical analysis of post-ablation defects after IRE for prostate cancer. Remaining tumor can be detected with the help of pseudo-colors.