Cardiovasc Intervent Radiol DOI 10.1007/s00270-014-1049-0
CLINICAL INVESTIGATION
Irreversible Electroporation (IRE) Fails to Demonstrate Efficacy in a Prospective Multicenter Phase II Trial on Lung Malignancies: The ALICE Trial Jens Ricke • Julian H. W. Ju¨rgens • Frederic Deschamps • Lambros Tselikas • Katja Uhde • Ortrud Kosiek • Thierry De Baere
Received: 14 July 2014 / Accepted: 11 December 2014 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2015
Abstract Purpose To assess safety and efficacy of irreversible electroporation (IRE) of lung malignancies. Materials and Methods Patients with primary and secondary lung malignancies and preserved lung function were included in this prospective single arm trial. Primary and secondary endpoints were safety and efficacy. Recruitment goal was 36 subjects in 2 centers. Patients underwent IRE under general anesthesia with probe placement performed in Fluoroscopy-CT. The IRE system employed was NanoKnifeÒ (Angiodynamics). System settings for the ablation procedure followed the manufacturer’s recommendations. The Mann–Whitney U test was used to evaluate the correlation of nine technical parameters with local tumor control. Median follow up was 12 months. Results The expected efficacy was not met at interim analysis and the trial was stopped prematurely after inclusion of 23 patients (13/10 between both centers). The dominant tumor entity was colorectal (n = 13). The median tumor diameter was 16 mm (8–27 mm). Pneumothoraces were observed in 11 of 23 patients with chest tubes required in 8 (35 %). Frequently observed alveolar hemorrhage never led to significant hemoptysis. 14/23 showed progressive disease (61 %). Stable disease was found in 1 J. Ricke (&) J. H. W. Ju¨rgens K. Uhde O. Kosiek Department of Radiology and Nuclear Medicine, University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany e-mail: [email protected] J. H. W. Ju¨rgens e-mail: [email protected] F. Deschamps L. Tselikas T. De Baere Department of Image Guided Therapy, Institut de Cance´rologie Gustave Roussy, Villejuif, France
(4 %), partial remission in 1 (4 %) and complete remission in 7 (30 %) patients. The relative increase of the current during ablation was significantly higher in the group treated successfully as compared to the group presenting local recurrence (p \ 0.05). Needle tract seeding was found in three cases (13 %). Conclusions IRE is not effective for the treatment of lung malignancies. We hypothesize that the energy deposition with current IRE probes is highly sensitive to air exposure. Keywords Interventional oncology Non-vascular interventions Irreversible electroporation (IRE) Lung/pulmonary Cancer
Introduction Irreversible electroporation (IRE) has found increasing interest since its first use in animal models [1, 2]. Electroporation is a technique that exposes cells to electric pulses. Its effects may be reversible or irreversible depending on the applied voltage [3–5]. Previous reports on IRE have described reproducible ablation zones with clear delineation of necrotic areas in a multitude of tumors or hosting organs such as liver, kidneys, lung, prostate, pancreas, and others [6–11]. In histopathology studies of resected specimen derived from animal models it has been shown that despite the induction of apoptosis and necrosis in soft tissue, structures containing a collagenous matrix such as bile duct, blood vessels, or renal pelvis remain functionally intact [6, 12–14]. However, the technique is premature in several key aspects. Technical endpoints for treatment success have not been described yet. Treatment parameters applied for the approved indication ‘‘soft tissue ablation’’ have been
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developed in ex vivo models, and data on their clinical validation is limited to small patient cohorts. Most of these small phase II cohorts do not represent prospective data but rather retrospective reports, and details of the technical parameters and machine settings applied are not indicated in most publications. Local ablation of lung malignancies by thermal ablation is a widely used alternative to thoracic surgery [15–17]. In thermal tumor ablation it has been reported that local tumor control suffers from adjacent large vessels due to heat sink effects [18]. In lung ablation, central tumors are challenging for thermal ablation due to the presence of large vessels as well as central bronchial structures which must be preserved. In addition, specifically in COPD or emphysematous patients local tumor control after thermal ablation tends to be lower compared to healthy lung. This effect possibly is related to thermal insulation by air or diminished conductivity when applying RFA. It might be less of a problem in MWA [19, 20]. Conclusive reports on the use of IRE in lung malignancies are not available today. The study described herein sought to determine the safety of this technique when applied to lung malignancies. In addition, we hoped to gather preliminary data on efficacy. However, at interim analysis after 23 patients almost equally distributed between two participating institutions, IRE of the lung failed to demonstrate efficacy and the study was terminated prematurely. In the following we report the study data.
Table 1 Patient characteristics N Gender Male
14
Female
9
Tumor biology CRC
13
CCC
2
Renal cell
2
NSCLC
2
Melanoma
1
Laryngeal cancer
1
Pancreatic cancer Thyroid cancer
1 1
Age
62 years (±12); range 39–81 years
Max. diameter of target lesion
16 mm (±5); range 8–27 mm
Diameter of the largest vessel within of the target lesion
5 mm (±6); range 1.0–30.0 mm
arrhythmia, no pacemaker, and a tumor size between 7 and 30 mm. At screening, proof of malignancy was accepted by positive histopathology, increased FDG uptake at PET-CT, or lesion growth at subsequent follow up visits. Patient Characteristics
Materials and Methods Study Design and Eligibility Criteria Primary endpoint of this exploratory, prospective single arm investigator initiated study was safety of IRE of the lung. Secondary endpoints included local control at 3 and 12 months stratified for adjacent lung vessels as well as tumor biology. The study protocol was submitted in identical versions to the institutional review boards of the participating two institutions in France and Germany. Both institutional review boards approved the study as such, as well as the planned data pooling following independent patient recruitment. All patients provided written informed consent before inclusion. Eligibility criteria included primary or secondary lung malignancies, normal lung function [forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) [80 % normal limits], at least 2 cm distance between target lesion and heart, no implants \1 cm to the target lesion, no history of epilepsia, cardiac infarction or
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Accrual goal was 36 lesions. However, the study was stopped prematurely after inclusion of 23 patients with 23 lesions (10/13 between the two centers) when an interim analysis revealed a failure of efficacy. Details of the patient characteristics are shown in Table 1. All patients displayed FEV1 and FVC [ 80 % of normal limits. Two patients had undergone previous lung surgery in the treated lung, two patients had undergone previous radiofrequency ablation in the treated lung (but not in the same pulmonary lobe) and two patients had undergone previous surgery and radiofrequency ablation in the ipsilateral lung. Interventional Technique and Machine Settings After induction of general anesthesia and positioning of the patient on the CT table (Germany: Aquilion 16, Toshiba; France: LightSpeed 16, GE), a plain reference CT scan was acquired. Under CT fluoroscopy, the IRE probes were inserted into the target volume. Final ablation planning was done employing an unenhanced, high resolution CT scan of
J. Ricke et al.: The ALICE Trial
the target volume after probe positioning. If the needle positions were considered suboptimal in regard to the distance to each other (10–22 mm), re-positioning of the needles and re-acquisition of the planning CT scan was performed. In no case the probes were positioned outside of the tumors; however, owing to the spherical shape of all lesions, the tip and the proximal part of the active probe reached into lung tissue. Immediately after termination of the ablation the probes were removed. Five minutes after removal of the probes, a lung scan was acquired to rule out pneumothorax. The IRE system employed was NanoKnifeÒ (Angiodynamics, Latham, USA). Multi-planar reconstruction of CT data was performed to adjust the three resulting planes to the orientation of the probes: For ablation planning a plane orthogonal to the orientation of the needles was used. In this plane, the tumor diameter, the distances between each probe pair and the distances from the probes to the tumor margin were measured. With these values, ablation planning was done with the NanoKnife’s ablation planning tool. We always applied a safety margin of 5 mm. The system settings for the ablation procedure followed the manufacturer’s recommendations and the porcine data for lung IRE [21]. 90 pulses (in groups of 10) with a pulse length of 70 ls were applied through each probe pair. The first ablation cycle was done with 1,500 V/cm varying with the probe distance up to 3,000 V per pulse (which is the maximum voltage applicable by the NanoKnife generator). When an overcurrent error occurred or the pulse delivery was terminated by the generator, the applied voltage was lowered and the aborted application was restarted. In case the maximum resulting current remained below 10 A, the ablation was repeated. The system used synchronized pulse delivery by ECG triggering to rule out potentially fatal ventricular arrhythmias [22, 23]. The pulse delivery was synchronized to the R wave of the ECG using an AccuSync 72 synchronization device (AccuSync Medical Research Corporation, Milford, Connecticut, USA) for each pulse delivery.
was performed with a reconstructed slice thickness of 1 mm. In French patients, no contrast media was used. The reconstruction algorithm was identical at 1 mm. In both centers PET/CT was performed using F18-FDG and a dedicated PET/CT-device (Biograph mCT 64Ò; Siemens Healthcare, Erlangen, Germany). Patients fasted for at least 6 h prior to the PET/CT scan. A test of blood glucose levels prior to tracer administration was mandatory to assure that the blood glucose level was below 150 mg/dl. Whole-body imaging was performed from the vertex to the proximal femora. A low-dose CT was performed for attenuation correction and anatomical mapping. Preinterventional CT for treatment planning never was older than 4 weeks. Baseline CT was acquired at 4 weeks and every 3 months post-intervention. FDG PET/CT (in patients qualifying) was acquired up to 4 weeks before the intervention and at 3 months. Supplemental clinical visits were scheduled at each follow up imaging visit. Tumor progression assessments in CT followed RECIST 1.1 criteria. Tumor progression in FDG–PET employed the PERCIST definition with response defined as a reduction of the SUV (standard uptake value) over time of [30 % [24]. Lung function assessments were only conducted if clinical evaluation made respiratory deficits likely. Alike, specific blood samples (e.g., myocardial enzymes) were only drawn if clinical symptoms had raised suspicion of unfaithful events.
General Anesthesia and Relaxation
Umin
A complete neuromuscular blockade was applied during anesthesia to avoid severe muscular contractions induced by the electric pulses of up to 3,000 V [22]. Complete muscular relaxation was controlled by neuromuscular monitoring.
Definitions To assess parameters potentially determining treatment success during or immediately after the ablation we performed an analysis of the following factors and their correlation with response: Nr of electrodes Ablation pairs
Umax
Follow Up and Assessment of Local Tumor Control In the German center follow up examinations always included contrast enhanced CT. Fifty five seconds after administration of 90 ml of contrast media a multislice CT
Istart
max
Count of electrodes inserted during the ablation. Count of electrode pairs used (maximum of possible pairs = nðn1Þ 2 with n = count of inserted electrodes). Lowest voltage applied during an ablation process in volts (If the number of ablation pairs was [ 1, the lowest value of all ablation pairs was used). Highest voltage applied during an ablation process in volts (If ablation pairs [1 or more, one ablation cycle was performed, the highest value of all ablation pairs or cycles was used). Highest current at the beginning of an ablation process in amperes (If the number of ablation pairs was [1 or
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J. Ricke et al.: The ALICE Trial Table 2 Technical parameters and response Parameter
Local recurrence (n = 14) Mean (Min–Max)
Nr of electrodes
No local recurrence (n = 9) Mean (Min–Max)
3.00 (2–6)
Ablation pairs
3.11 (2–6)
2.64 (1–6)
2.89 (1–6)
Umin (V)
1866.43 (1,000–3,000)
1741.67 (900–3,000)
Umax (V) Istart Iend
0.829 0.877 0.439
2694.29 (1,800–3,000)
2477.78 (1,800–3,000)
0.477
(A)
25.89 (5.31–50.20)
22.09 (9.94–43.12)
0.305
(A)
32.48 (10.13–50.20)
32.44 (14.95–50.20)
0.877
8.52 (2.20–16.50) 44.57 (18.12–90.77)
12.71 (3.67–24.48) 74.91 (28.75–109.83)
0.201 0.028
max max
p
DIabs max (A) DIrel max (%) Pulses per pair
128.81 (70–180)
147.78 (90–260)
0.439
See ‘‘Materials and Methods’’ section for detailed definitions of the parameters chosen
Iend
max
DIabs
DIrel
max
max
Pulses per pair
more than one ablation cycle was performed, the highest value of all ablation pairs or cycles was used). Highest current at the end of an ablation process in amperes (If the number of ablation pairs was [1 or more than one ablation cycle was performed, the highest value of all ablation pairs or cycles was used). Highest absolute difference of the current between start and end of an ablation cycle in amperes. If more than one ablation cycle with the same voltage was performed, the difference was calculated between the resulting current at the start of the first cycle and the end of the last cycle. (If the number of ablation pairs was [1 or more than one ablation cycle with different voltages was performed, the highest value of all ablation pairs or cycles was used). Same as DIabs max but as a relative value in percent. Mean count of pulses applied per ablation pair (=Overall count of pulses applied during an ablation process divided by ‘‘Ablation pairs’’).
defined as either ‘‘progressive disease’’ according to RECIST 1.1 or proven by biopsy. Due to the small sample size no standard distribution was assumed. Therefore, a univariate analysis was performed for each individual parameter using the Mann–Whitney U test. The significance level was set at p \ 0.05. Since only one parameter showed a significant result, no multivariate analysis was added (Table 2).
Results Median follow up was 12 months (3–24 months). We performed 23 interventions (10 France, 13 Germany) in 23 patients before the study was terminated early. The number of electrodes used was 3 at median (2–6 probes). The duration of the intervention as exemplified by duration of anesthesia (minutes from ‘‘begin induction of anesthesia’’ to ‘‘removal of the tube’’) was 140 min at median (70–215 min). The time from ‘‘insertion of the first probe’’ to ‘‘removal of the last probe’’) was 72 min at median (27–155). Adverse Events Pneumothorax was observed in 11 of 23 patients (48 %) with a chest tube required in 8 (35 %). Frequently observed alveolar hemorrhage never led to significant hemoptysis. No other adverse events were recorded.
Statistical Methods
Response to Treatment
Patient and treatment characteristics as well as treatment response were recorded descriptively. The Mann–Whitney U test was used to assess the correlation between nine technical parameters and local tumor control. Nine technical parameters were analyzed independently for presence or absence of a local recurrence. Local recurrence was
CT assessment of all 23 patients revealed complete responses (CRs) in 7 of 23 lesions (30 %), partial response (PR) in 1 (4 %), stable disease (SD) in 1 (4 %), and progressive disease (PD) in 14 (61 %). PET/CT was performed at baseline and after 3 months in 12 out of 23 patients displaying 12 lesions. In these
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J. Ricke et al.: The ALICE Trial b Fig. 1 A, B Needle tract seeding 3 months post-intervention. Inter-
ventional CT shows probe position (A). Small inserts represent needle tract seeding at 3 months (B) and at 12 months next to local tumor progression (C)
Fig. 2 Size of the largest vessel within 1 cm from the target lesion versus local recurrence (Yes/No) p = 0.072
patients, only one showed a relative SUV reduction [30 % (Partial or CR in 1 out of 12, 8 %) However, no correlation was found between SUV reduction and CT assessments of local recurrence (p = 0.368). Needle tract seeding was found in 3 out of 23 cases (13 %) with all those lesions developing in lung parenchyma (Fig. 1A–C). Technical and Clinical Parameters Predicting Response To assess predictors of response we measured the diameter of the largest adjacent vessel within 1 cm of the target lesion. Even though the Mann–Whitney U test failed to demonstrate significance a trend to higher local recurrence rates adjacent to larger vessels was obvious (p = 0.072) (Fig. 2). Table 2 demonstrates the results of the technical parameters tested against response. Out of all parameters tested, only the relative increase of the current during ablation was significantly higher in the group treated successfully as compared to the group presenting local recurrence (p \ 0.05).
Discussion To the best of our knowledge this is the first controlled study determining the safety and efficacy of IRE of lung malignancies. The technique failed to demonstrate efficacy
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with a local control rate of only 39 % (including CR, PR, SD) in tumors from 8 to 27 mm. Consequently, the study which initially had been designed to recruit 36 lesions was terminated prematurely. The very high local failure of IRE in the treatment of lung malignancies was an unexpected result in light of studies on IRE applied in other tumor locations with greater success. As an example, Scheffer et al. included 10 patients with resectable colorectal liver metastases. During laparotomy, the metastases were treated with IRE and resected 60 min later. Tissue response was assessed using vitality and histochemical stainings. A complete cell death was demonstrated in all tumors despite the comparatively small time interval to resection [25]. With respect to IRE of lung tumors, only two case series reporting the treatment of eight lesions in six patients have been published in parallel to our study [26, 27]. All lesions were reported progressive at follow up. It has been noted by several authors that the treatment effect of IRE is susceptible to tissue properties influencing electric conductivity [28]. Lung tissue is not dense and causes significant impedance of current flow. In addition, air is a strong insulator. The device functions by creating couplets with energy flowing from one probe to the next. As a result, the cytotoxic effect of electroporation is limited peripherally to the probes [29]. Hence, the probe positions must be in the periphery of a given tumor. Due to the spherical geometry, parts of the probe inevitably reach lung tissue if placed laterally. As a consequence, a homogenous electric field between two electrodes and consequently the effective ablation of tumors in the lung cannot be guaranteed. IRE is widely described as a non-thermal ablation, thus damaging only cellular tissues and leaving the collagenous matrix of tissues such as bile duct or vessels unharmed [30, 31]. However, a recent publication suggested that thermal changes may be more frequent and may even induce locally confined tissue destruction [32]. In our own study, the presence of large blood vessels adjacent to the tumor volume demonstrated a trend towards a negative outcome of local control (p = 0.072). In light of the data by Faroja et al. [32] one might argue a thermal effect contributes to better tumor destruction with IRE. However, in our eyes a change of tissue conductivity disturbing the homogeneity of the electric field adjacent to large blood vessels may better explain a potential negative effect on local control. Further studies are warranted to assess whether large blood vessels are a predictor of negative outcome after IRE. One of the shortcomings of IRE today is the absence of dedicated, clinically validated protocols to be used in different tissue environments and tumor biology [28]. In addition, no technical endpoint has been described so far which reliably predicts successful ablation of a tumor
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during the ongoing intervention. We assessed a variety of technical parameters potentially correlated with outcome. Only the relative increase of the current during an ablation process correlated significantly with local tumor control in malignant lung lesions. IRE leads to an opening of small pores in the cell membrane [30]. As a consequence, the cell membrane is no longer a barrier for ions. Hence, an initial electrical isolation based on the cell membranes vanishes during IRE. The impedance of the tissue between the electrodes decreases and the current increases gradually if the ablation is successful. We suggest that further clinical studies should validate the relative increase of the current during an ablation process as a potential technical endpoint for successful ablation. IRE generally proved to be safe when applied in lung tumors. One of the drawbacks of the technique is the requirement to position a multitude of up to six probes in a parallel array at a distance of about 10 mm to a maximum of 22 mm. The parallel alignment of the probes in the lung is challenging due to the interposition of the ribs. The probes have a much smaller diameter as compared to RFA electrodes or MWA antennas, which may limit the trauma when approaching the tumor through lung tissue; however, accurate steering of these soft applicators under CT guidance into the required small target window is demanding. Hence, placement of the probes may necessitate more than one passage for each probe. As a result the rate of pneumothorax was high at 48 % with the majority of patients (8 out of 23, 35 %) requiring chest tubes. Data published on RFA is inconsistent in regard to the incidence of pneumothorax ranging from 3 to 40 % [33]; however, a recent publication on a patient cohort of [400 and 1,000 interventions demonstrated a chest tube frequency of around 4 % only [34]. Another potential disadvantage of IRE as compared to thermal ablation techniques may be that the needle tract is not sealed upon withdrawal of the multiple probes. Hemorrhage or hemoptysis was never a problem. However, in our patient cohort we detected needle tract seeding in 3 out of 23 patients (13 %). We have not found similar descriptions in the literature on lung RFA or MWA where track ablation is a standard procedure. It must be noted that needle tract seeding was only found in patients from the German institution. In these patients, we did not pull back the needle tip into the cover before removing the needles from the tumor (an insulation cover determines the exposed needle tip length of up to 4 cm. Normally, the needle enters the tumor, and the cover is then pulled back after positioning of the needle tip. For withdrawal, one may cover the tip again). It is unclear whether covering the needle tip upon withdrawal would have positively influenced the risk of seeding. We suggest an investigation of needle tract seeding in other IRE indications such as liver tumor
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ablation as well. The potential methodological pitfall of not pulling the needle back into the cover should be considered. In summary, IRE failed to prove efficacy in lung tumors. In IRE not only the tumor entity determines successful treatment, but properties of the surrounding tissue do have strong impact on the outcome. The technique has shown promising results in other tissues baring malignancies such as liver; however, standardized technical parameters for ablation in different locations are not yet validated and an appropriate technical endpoint for successful tumor destruction is still missing. Conflict of interest Jens Ricke, Julian Ju¨rgens, Frederic Deschamps, Lambros Tselikas, Katja Uhde, Ortrud Kosiek, and Thierry De Baere have no conflict of interest. Statement of Human and Animal Rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Statement of Informed Consent Informed consent was obtained from all individual participants included in the study.
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12. Wendler JJ, Pech M, Blaschke S et al (2012) Angiography in the isolated perfused kidney: radiological evaluation of vascular protection in tissue ablation by nonthermal irreversible electroporation. Cardiovasc Interv Radiol 35:383–390 13. Wendler JJ, Pech M, Porsch M et al (2012) Urinary tract effects after multifocal nonthermal irreversible electroporation of the kidney: acute and chronic monitoring by magnetic resonance imaging, intravenous urography and urinary cytology. Cardiovasc Interv Radiol 35:921–926 14. Wendler JJ, Porsch M, Huhne S et al (2013) Short- and mid-term effects of irreversible electroporation on normal renal tissue: an animal model. Cardiovasc Interv Radiol 36:512–520 15. Little MW, Chung D, Boardman P, Gleeson FV, Anderson EM (2013) Microwave ablation of pulmonary malignancies using a novel high-energy antenna system. Cardiovasc Interv Radiol 36:460–465 16. Yan TD, King J, Sjarif A, Glenn D, Steinke K, Morris DL (2006) Percutaneous radiofrequency ablation of pulmonary metastases from colorectal carcinoma: prognostic determinants for survival. Ann Surg Oncol 13:1529–1537 17. Lencioni R, Crocetti L, Cioni R et al (2008) Response to radiofrequency ablation of pulmonary tumours: a prospective, intention-to-treat, multicentre clinical trial (the RAPTURE study). Lancet Oncol 9:621–628 18. Lu DS, Yu NC, Raman SS et al (2005) Radiofrequency ablation of hepatocellular carcinoma: treatment success as defined by histologic examination of the explanted liver. Radiology 234:954–960 19. Lee H, Jin GY, Han YM et al (2012) Comparison of survival rate in primary non-small-cell lung cancer among elderly patients treated with radiofrequency ablation, surgery, or chemotherapy. Cardiovasc Interv Radiol 35:343–350 20. Bilal H, Mahmood S, Rajashanker B, Shah R (2012) Is radiofrequency ablation more effective than stereotactic ablative radiotherapy in patients with early stage medically inoperable non-small cell lung cancer? Interact CardioVasc Thorac Surg 15:258–265 21. Deodhar A, Monette S, Single GW Jr et al (2011) Percutaneous irreversible electroporation lung ablation: preliminary results in a porcine model. Cardiovasc Interv Radiol 34:1278–1287 22. Ball C, Thomson KR, Kavnoudias H (2010) Irreversible electroporation: a new challenge in ‘‘out of operating theater’’ anesthesia. Anesth Analg 110:1305–1309 23. Deodhar A, Dickfeld T, Single GW et al (2011) Irreversible electroporation near the heart: ventricular arrhythmias can be prevented with ECG synchronization. AJR Am J Roentgenol 196:W330–W335 24. Wahl RL, Jacene H, Kasamon Y, Lodge MA (2009) From RECIST to PERCIST: evolving considerations for PET response criteria in solid tumors. J Nucl Med 50(Suppl 1):122S–150S 25. Scheffer HJ, Nielsen K, van Tilborg AA et al (2014) Ablation of colorectal liver metastases by irreversible electroporation: results of the COLDFIRE-I ablate-and-resect study. Eur Radiol 24(10):2467–2475 26. Thomson KR, Cheung W, Ellis SJ et al (2011) Investigation of the safety of irreversible electroporation in humans. J Vasc Interv Radiol 22:611–621 27. Usman M, Moore W, Talati R, Watkins K, Bilfinger TV (2012) Irreversible electroporation of lung neoplasm: a case series. Med Sci Monit 18:CS43–CS47 28. Ben-David E, Ahmed M, Faroja M et al (2013) Irreversible electroporation: treatment effect is susceptible to local environment and tissue properties. Radiology 269:738–747 29. Davalos RV, Mir IL, Rubinsky B (2005) Tissue ablation with irreversible electroporation. Ann Biomed Eng 33:223–231
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CLINICAL INVESTIGATION
Irreversible Electroporation (IRE) Fails to Demonstrate Efficacy in a Prospective Multicenter Phase II Trial on Lung Malignancies: The ALICE Trial Jens Ricke • Julian H. W. Ju¨rgens • Frederic Deschamps • Lambros Tselikas • Katja Uhde • Ortrud Kosiek • Thierry De Baere
Received: 14 July 2014 / Accepted: 11 December 2014 Ó Springer Science+Business Media New York and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) 2015
Abstract Purpose To assess safety and efficacy of irreversible electroporation (IRE) of lung malignancies. Materials and Methods Patients with primary and secondary lung malignancies and preserved lung function were included in this prospective single arm trial. Primary and secondary endpoints were safety and efficacy. Recruitment goal was 36 subjects in 2 centers. Patients underwent IRE under general anesthesia with probe placement performed in Fluoroscopy-CT. The IRE system employed was NanoKnifeÒ (Angiodynamics). System settings for the ablation procedure followed the manufacturer’s recommendations. The Mann–Whitney U test was used to evaluate the correlation of nine technical parameters with local tumor control. Median follow up was 12 months. Results The expected efficacy was not met at interim analysis and the trial was stopped prematurely after inclusion of 23 patients (13/10 between both centers). The dominant tumor entity was colorectal (n = 13). The median tumor diameter was 16 mm (8–27 mm). Pneumothoraces were observed in 11 of 23 patients with chest tubes required in 8 (35 %). Frequently observed alveolar hemorrhage never led to significant hemoptysis. 14/23 showed progressive disease (61 %). Stable disease was found in 1 J. Ricke (&) J. H. W. Ju¨rgens K. Uhde O. Kosiek Department of Radiology and Nuclear Medicine, University of Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany e-mail: [email protected] J. H. W. Ju¨rgens e-mail: [email protected] F. Deschamps L. Tselikas T. De Baere Department of Image Guided Therapy, Institut de Cance´rologie Gustave Roussy, Villejuif, France
(4 %), partial remission in 1 (4 %) and complete remission in 7 (30 %) patients. The relative increase of the current during ablation was significantly higher in the group treated successfully as compared to the group presenting local recurrence (p \ 0.05). Needle tract seeding was found in three cases (13 %). Conclusions IRE is not effective for the treatment of lung malignancies. We hypothesize that the energy deposition with current IRE probes is highly sensitive to air exposure. Keywords Interventional oncology Non-vascular interventions Irreversible electroporation (IRE) Lung/pulmonary Cancer
Introduction Irreversible electroporation (IRE) has found increasing interest since its first use in animal models [1, 2]. Electroporation is a technique that exposes cells to electric pulses. Its effects may be reversible or irreversible depending on the applied voltage [3–5]. Previous reports on IRE have described reproducible ablation zones with clear delineation of necrotic areas in a multitude of tumors or hosting organs such as liver, kidneys, lung, prostate, pancreas, and others [6–11]. In histopathology studies of resected specimen derived from animal models it has been shown that despite the induction of apoptosis and necrosis in soft tissue, structures containing a collagenous matrix such as bile duct, blood vessels, or renal pelvis remain functionally intact [6, 12–14]. However, the technique is premature in several key aspects. Technical endpoints for treatment success have not been described yet. Treatment parameters applied for the approved indication ‘‘soft tissue ablation’’ have been
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developed in ex vivo models, and data on their clinical validation is limited to small patient cohorts. Most of these small phase II cohorts do not represent prospective data but rather retrospective reports, and details of the technical parameters and machine settings applied are not indicated in most publications. Local ablation of lung malignancies by thermal ablation is a widely used alternative to thoracic surgery [15–17]. In thermal tumor ablation it has been reported that local tumor control suffers from adjacent large vessels due to heat sink effects [18]. In lung ablation, central tumors are challenging for thermal ablation due to the presence of large vessels as well as central bronchial structures which must be preserved. In addition, specifically in COPD or emphysematous patients local tumor control after thermal ablation tends to be lower compared to healthy lung. This effect possibly is related to thermal insulation by air or diminished conductivity when applying RFA. It might be less of a problem in MWA [19, 20]. Conclusive reports on the use of IRE in lung malignancies are not available today. The study described herein sought to determine the safety of this technique when applied to lung malignancies. In addition, we hoped to gather preliminary data on efficacy. However, at interim analysis after 23 patients almost equally distributed between two participating institutions, IRE of the lung failed to demonstrate efficacy and the study was terminated prematurely. In the following we report the study data.
Table 1 Patient characteristics N Gender Male
14
Female
9
Tumor biology CRC
13
CCC
2
Renal cell
2
NSCLC
2
Melanoma
1
Laryngeal cancer
1
Pancreatic cancer Thyroid cancer
1 1
Age
62 years (±12); range 39–81 years
Max. diameter of target lesion
16 mm (±5); range 8–27 mm
Diameter of the largest vessel within of the target lesion
5 mm (±6); range 1.0–30.0 mm
arrhythmia, no pacemaker, and a tumor size between 7 and 30 mm. At screening, proof of malignancy was accepted by positive histopathology, increased FDG uptake at PET-CT, or lesion growth at subsequent follow up visits. Patient Characteristics
Materials and Methods Study Design and Eligibility Criteria Primary endpoint of this exploratory, prospective single arm investigator initiated study was safety of IRE of the lung. Secondary endpoints included local control at 3 and 12 months stratified for adjacent lung vessels as well as tumor biology. The study protocol was submitted in identical versions to the institutional review boards of the participating two institutions in France and Germany. Both institutional review boards approved the study as such, as well as the planned data pooling following independent patient recruitment. All patients provided written informed consent before inclusion. Eligibility criteria included primary or secondary lung malignancies, normal lung function [forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) [80 % normal limits], at least 2 cm distance between target lesion and heart, no implants \1 cm to the target lesion, no history of epilepsia, cardiac infarction or
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Accrual goal was 36 lesions. However, the study was stopped prematurely after inclusion of 23 patients with 23 lesions (10/13 between the two centers) when an interim analysis revealed a failure of efficacy. Details of the patient characteristics are shown in Table 1. All patients displayed FEV1 and FVC [ 80 % of normal limits. Two patients had undergone previous lung surgery in the treated lung, two patients had undergone previous radiofrequency ablation in the treated lung (but not in the same pulmonary lobe) and two patients had undergone previous surgery and radiofrequency ablation in the ipsilateral lung. Interventional Technique and Machine Settings After induction of general anesthesia and positioning of the patient on the CT table (Germany: Aquilion 16, Toshiba; France: LightSpeed 16, GE), a plain reference CT scan was acquired. Under CT fluoroscopy, the IRE probes were inserted into the target volume. Final ablation planning was done employing an unenhanced, high resolution CT scan of
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the target volume after probe positioning. If the needle positions were considered suboptimal in regard to the distance to each other (10–22 mm), re-positioning of the needles and re-acquisition of the planning CT scan was performed. In no case the probes were positioned outside of the tumors; however, owing to the spherical shape of all lesions, the tip and the proximal part of the active probe reached into lung tissue. Immediately after termination of the ablation the probes were removed. Five minutes after removal of the probes, a lung scan was acquired to rule out pneumothorax. The IRE system employed was NanoKnifeÒ (Angiodynamics, Latham, USA). Multi-planar reconstruction of CT data was performed to adjust the three resulting planes to the orientation of the probes: For ablation planning a plane orthogonal to the orientation of the needles was used. In this plane, the tumor diameter, the distances between each probe pair and the distances from the probes to the tumor margin were measured. With these values, ablation planning was done with the NanoKnife’s ablation planning tool. We always applied a safety margin of 5 mm. The system settings for the ablation procedure followed the manufacturer’s recommendations and the porcine data for lung IRE [21]. 90 pulses (in groups of 10) with a pulse length of 70 ls were applied through each probe pair. The first ablation cycle was done with 1,500 V/cm varying with the probe distance up to 3,000 V per pulse (which is the maximum voltage applicable by the NanoKnife generator). When an overcurrent error occurred or the pulse delivery was terminated by the generator, the applied voltage was lowered and the aborted application was restarted. In case the maximum resulting current remained below 10 A, the ablation was repeated. The system used synchronized pulse delivery by ECG triggering to rule out potentially fatal ventricular arrhythmias [22, 23]. The pulse delivery was synchronized to the R wave of the ECG using an AccuSync 72 synchronization device (AccuSync Medical Research Corporation, Milford, Connecticut, USA) for each pulse delivery.
was performed with a reconstructed slice thickness of 1 mm. In French patients, no contrast media was used. The reconstruction algorithm was identical at 1 mm. In both centers PET/CT was performed using F18-FDG and a dedicated PET/CT-device (Biograph mCT 64Ò; Siemens Healthcare, Erlangen, Germany). Patients fasted for at least 6 h prior to the PET/CT scan. A test of blood glucose levels prior to tracer administration was mandatory to assure that the blood glucose level was below 150 mg/dl. Whole-body imaging was performed from the vertex to the proximal femora. A low-dose CT was performed for attenuation correction and anatomical mapping. Preinterventional CT for treatment planning never was older than 4 weeks. Baseline CT was acquired at 4 weeks and every 3 months post-intervention. FDG PET/CT (in patients qualifying) was acquired up to 4 weeks before the intervention and at 3 months. Supplemental clinical visits were scheduled at each follow up imaging visit. Tumor progression assessments in CT followed RECIST 1.1 criteria. Tumor progression in FDG–PET employed the PERCIST definition with response defined as a reduction of the SUV (standard uptake value) over time of [30 % [24]. Lung function assessments were only conducted if clinical evaluation made respiratory deficits likely. Alike, specific blood samples (e.g., myocardial enzymes) were only drawn if clinical symptoms had raised suspicion of unfaithful events.
General Anesthesia and Relaxation
Umin
A complete neuromuscular blockade was applied during anesthesia to avoid severe muscular contractions induced by the electric pulses of up to 3,000 V [22]. Complete muscular relaxation was controlled by neuromuscular monitoring.
Definitions To assess parameters potentially determining treatment success during or immediately after the ablation we performed an analysis of the following factors and their correlation with response: Nr of electrodes Ablation pairs
Umax
Follow Up and Assessment of Local Tumor Control In the German center follow up examinations always included contrast enhanced CT. Fifty five seconds after administration of 90 ml of contrast media a multislice CT
Istart
max
Count of electrodes inserted during the ablation. Count of electrode pairs used (maximum of possible pairs = nðn1Þ 2 with n = count of inserted electrodes). Lowest voltage applied during an ablation process in volts (If the number of ablation pairs was [ 1, the lowest value of all ablation pairs was used). Highest voltage applied during an ablation process in volts (If ablation pairs [1 or more, one ablation cycle was performed, the highest value of all ablation pairs or cycles was used). Highest current at the beginning of an ablation process in amperes (If the number of ablation pairs was [1 or
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J. Ricke et al.: The ALICE Trial Table 2 Technical parameters and response Parameter
Local recurrence (n = 14) Mean (Min–Max)
Nr of electrodes
No local recurrence (n = 9) Mean (Min–Max)
3.00 (2–6)
Ablation pairs
3.11 (2–6)
2.64 (1–6)
2.89 (1–6)
Umin (V)
1866.43 (1,000–3,000)
1741.67 (900–3,000)
Umax (V) Istart Iend
0.829 0.877 0.439
2694.29 (1,800–3,000)
2477.78 (1,800–3,000)
0.477
(A)
25.89 (5.31–50.20)
22.09 (9.94–43.12)
0.305
(A)
32.48 (10.13–50.20)
32.44 (14.95–50.20)
0.877
8.52 (2.20–16.50) 44.57 (18.12–90.77)
12.71 (3.67–24.48) 74.91 (28.75–109.83)
0.201 0.028
max max
p
DIabs max (A) DIrel max (%) Pulses per pair
128.81 (70–180)
147.78 (90–260)
0.439
See ‘‘Materials and Methods’’ section for detailed definitions of the parameters chosen
Iend
max
DIabs
DIrel
max
max
Pulses per pair
more than one ablation cycle was performed, the highest value of all ablation pairs or cycles was used). Highest current at the end of an ablation process in amperes (If the number of ablation pairs was [1 or more than one ablation cycle was performed, the highest value of all ablation pairs or cycles was used). Highest absolute difference of the current between start and end of an ablation cycle in amperes. If more than one ablation cycle with the same voltage was performed, the difference was calculated between the resulting current at the start of the first cycle and the end of the last cycle. (If the number of ablation pairs was [1 or more than one ablation cycle with different voltages was performed, the highest value of all ablation pairs or cycles was used). Same as DIabs max but as a relative value in percent. Mean count of pulses applied per ablation pair (=Overall count of pulses applied during an ablation process divided by ‘‘Ablation pairs’’).
defined as either ‘‘progressive disease’’ according to RECIST 1.1 or proven by biopsy. Due to the small sample size no standard distribution was assumed. Therefore, a univariate analysis was performed for each individual parameter using the Mann–Whitney U test. The significance level was set at p \ 0.05. Since only one parameter showed a significant result, no multivariate analysis was added (Table 2).
Results Median follow up was 12 months (3–24 months). We performed 23 interventions (10 France, 13 Germany) in 23 patients before the study was terminated early. The number of electrodes used was 3 at median (2–6 probes). The duration of the intervention as exemplified by duration of anesthesia (minutes from ‘‘begin induction of anesthesia’’ to ‘‘removal of the tube’’) was 140 min at median (70–215 min). The time from ‘‘insertion of the first probe’’ to ‘‘removal of the last probe’’) was 72 min at median (27–155). Adverse Events Pneumothorax was observed in 11 of 23 patients (48 %) with a chest tube required in 8 (35 %). Frequently observed alveolar hemorrhage never led to significant hemoptysis. No other adverse events were recorded.
Statistical Methods
Response to Treatment
Patient and treatment characteristics as well as treatment response were recorded descriptively. The Mann–Whitney U test was used to assess the correlation between nine technical parameters and local tumor control. Nine technical parameters were analyzed independently for presence or absence of a local recurrence. Local recurrence was
CT assessment of all 23 patients revealed complete responses (CRs) in 7 of 23 lesions (30 %), partial response (PR) in 1 (4 %), stable disease (SD) in 1 (4 %), and progressive disease (PD) in 14 (61 %). PET/CT was performed at baseline and after 3 months in 12 out of 23 patients displaying 12 lesions. In these
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J. Ricke et al.: The ALICE Trial b Fig. 1 A, B Needle tract seeding 3 months post-intervention. Inter-
ventional CT shows probe position (A). Small inserts represent needle tract seeding at 3 months (B) and at 12 months next to local tumor progression (C)
Fig. 2 Size of the largest vessel within 1 cm from the target lesion versus local recurrence (Yes/No) p = 0.072
patients, only one showed a relative SUV reduction [30 % (Partial or CR in 1 out of 12, 8 %) However, no correlation was found between SUV reduction and CT assessments of local recurrence (p = 0.368). Needle tract seeding was found in 3 out of 23 cases (13 %) with all those lesions developing in lung parenchyma (Fig. 1A–C). Technical and Clinical Parameters Predicting Response To assess predictors of response we measured the diameter of the largest adjacent vessel within 1 cm of the target lesion. Even though the Mann–Whitney U test failed to demonstrate significance a trend to higher local recurrence rates adjacent to larger vessels was obvious (p = 0.072) (Fig. 2). Table 2 demonstrates the results of the technical parameters tested against response. Out of all parameters tested, only the relative increase of the current during ablation was significantly higher in the group treated successfully as compared to the group presenting local recurrence (p \ 0.05).
Discussion To the best of our knowledge this is the first controlled study determining the safety and efficacy of IRE of lung malignancies. The technique failed to demonstrate efficacy
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with a local control rate of only 39 % (including CR, PR, SD) in tumors from 8 to 27 mm. Consequently, the study which initially had been designed to recruit 36 lesions was terminated prematurely. The very high local failure of IRE in the treatment of lung malignancies was an unexpected result in light of studies on IRE applied in other tumor locations with greater success. As an example, Scheffer et al. included 10 patients with resectable colorectal liver metastases. During laparotomy, the metastases were treated with IRE and resected 60 min later. Tissue response was assessed using vitality and histochemical stainings. A complete cell death was demonstrated in all tumors despite the comparatively small time interval to resection [25]. With respect to IRE of lung tumors, only two case series reporting the treatment of eight lesions in six patients have been published in parallel to our study [26, 27]. All lesions were reported progressive at follow up. It has been noted by several authors that the treatment effect of IRE is susceptible to tissue properties influencing electric conductivity [28]. Lung tissue is not dense and causes significant impedance of current flow. In addition, air is a strong insulator. The device functions by creating couplets with energy flowing from one probe to the next. As a result, the cytotoxic effect of electroporation is limited peripherally to the probes [29]. Hence, the probe positions must be in the periphery of a given tumor. Due to the spherical geometry, parts of the probe inevitably reach lung tissue if placed laterally. As a consequence, a homogenous electric field between two electrodes and consequently the effective ablation of tumors in the lung cannot be guaranteed. IRE is widely described as a non-thermal ablation, thus damaging only cellular tissues and leaving the collagenous matrix of tissues such as bile duct or vessels unharmed [30, 31]. However, a recent publication suggested that thermal changes may be more frequent and may even induce locally confined tissue destruction [32]. In our own study, the presence of large blood vessels adjacent to the tumor volume demonstrated a trend towards a negative outcome of local control (p = 0.072). In light of the data by Faroja et al. [32] one might argue a thermal effect contributes to better tumor destruction with IRE. However, in our eyes a change of tissue conductivity disturbing the homogeneity of the electric field adjacent to large blood vessels may better explain a potential negative effect on local control. Further studies are warranted to assess whether large blood vessels are a predictor of negative outcome after IRE. One of the shortcomings of IRE today is the absence of dedicated, clinically validated protocols to be used in different tissue environments and tumor biology [28]. In addition, no technical endpoint has been described so far which reliably predicts successful ablation of a tumor
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during the ongoing intervention. We assessed a variety of technical parameters potentially correlated with outcome. Only the relative increase of the current during an ablation process correlated significantly with local tumor control in malignant lung lesions. IRE leads to an opening of small pores in the cell membrane [30]. As a consequence, the cell membrane is no longer a barrier for ions. Hence, an initial electrical isolation based on the cell membranes vanishes during IRE. The impedance of the tissue between the electrodes decreases and the current increases gradually if the ablation is successful. We suggest that further clinical studies should validate the relative increase of the current during an ablation process as a potential technical endpoint for successful ablation. IRE generally proved to be safe when applied in lung tumors. One of the drawbacks of the technique is the requirement to position a multitude of up to six probes in a parallel array at a distance of about 10 mm to a maximum of 22 mm. The parallel alignment of the probes in the lung is challenging due to the interposition of the ribs. The probes have a much smaller diameter as compared to RFA electrodes or MWA antennas, which may limit the trauma when approaching the tumor through lung tissue; however, accurate steering of these soft applicators under CT guidance into the required small target window is demanding. Hence, placement of the probes may necessitate more than one passage for each probe. As a result the rate of pneumothorax was high at 48 % with the majority of patients (8 out of 23, 35 %) requiring chest tubes. Data published on RFA is inconsistent in regard to the incidence of pneumothorax ranging from 3 to 40 % [33]; however, a recent publication on a patient cohort of [400 and 1,000 interventions demonstrated a chest tube frequency of around 4 % only [34]. Another potential disadvantage of IRE as compared to thermal ablation techniques may be that the needle tract is not sealed upon withdrawal of the multiple probes. Hemorrhage or hemoptysis was never a problem. However, in our patient cohort we detected needle tract seeding in 3 out of 23 patients (13 %). We have not found similar descriptions in the literature on lung RFA or MWA where track ablation is a standard procedure. It must be noted that needle tract seeding was only found in patients from the German institution. In these patients, we did not pull back the needle tip into the cover before removing the needles from the tumor (an insulation cover determines the exposed needle tip length of up to 4 cm. Normally, the needle enters the tumor, and the cover is then pulled back after positioning of the needle tip. For withdrawal, one may cover the tip again). It is unclear whether covering the needle tip upon withdrawal would have positively influenced the risk of seeding. We suggest an investigation of needle tract seeding in other IRE indications such as liver tumor
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ablation as well. The potential methodological pitfall of not pulling the needle back into the cover should be considered. In summary, IRE failed to prove efficacy in lung tumors. In IRE not only the tumor entity determines successful treatment, but properties of the surrounding tissue do have strong impact on the outcome. The technique has shown promising results in other tissues baring malignancies such as liver; however, standardized technical parameters for ablation in different locations are not yet validated and an appropriate technical endpoint for successful tumor destruction is still missing. Conflict of interest Jens Ricke, Julian Ju¨rgens, Frederic Deschamps, Lambros Tselikas, Katja Uhde, Ortrud Kosiek, and Thierry De Baere have no conflict of interest. Statement of Human and Animal Rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Statement of Informed Consent Informed consent was obtained from all individual participants included in the study.
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