Irreversible electroporation (IRE) is a biophysical phenomenon in which cellular membranes exhibit increased permeability to ions and macromolecules when exposed to external electric fields. Although the exact mechanisms of electroporation have not been fully elucidated, the scientific community has mostly come to agreement that permeabilizing nanoscale defects or ‘‘nanopores’’ are formed in cellular membranes upon exposure to high-amplitude electric fields of sufficient duration. This phenomenon is manifested in 2 distinct forms: reversible electroporation, in which permeabilizing structures are transient and membrane integrity is quickly recovered; and IRE, in which permeabilization disrupts cellular homeostasis and leads to cell death.1
In 2005, Davalos, et al.2 proposed that IRE could be used as a stand-alone technique for soft tissue ablation. IRE delivers micro to millisecond electrical pulses to undesired tissue in order to produce cell necrosis through irreversible cell membrane permeabilization. IRE affects only the cell membrane and no other structure in the tissue. Over the ensuing years, IRE has been studied for its utility in cancer treatment, with and without combination of other modalities. There appears to be complete ablation to the margin of a treated lesion with several cell thickness of resolution. Thus, it was postulated that IRE could treat tumors without compromising nearby structures such as blood vessels, bile ducts, connective tissue, etc.
This minimally invasive procedure is performed under general anesthesia with ultrasound or computed tomography (CT) guidance and can be used during open or laparoscopic surgery or percutaneous procedures. IRE systems typically consist of a low-energy direct-current generator, a console with a monitor screen and control interface (e.g., keyboard and trackpad), a foot pedal to activate the system, and a set of needle electrode probes. During the procedure, 2 to 6 electrodes are placed around the target tumor, and a series of high-voltage, direct-current microsecond pulses create an electric field to induce cell electroporation.
There is limited literature to support such usage in cancers of the colon, pancreas, liver, prostate, kidney, and breast. This LCD will examine the evidence for the utility of IRE in the treatment of each of these 6 sites of cancer occurrences/metastases.
Colon Cancer
Colorectal cancer (CRC) is the third most common cancer worldwide, with 1.1 million new cases per year, and is the second leading cause of cancer death. CRC occurs more frequently in middle- to high-income countries with an eightfold variation in incidence across the world. Approximately 15%-30% of patients present with metastases, and 20%-50% of patients with initially localized disease will develop metastases. The most common location of metastases being liver, then lung, peritoneum, and distant lymph nodes.3
There are no published studies for the treatment of primary colon cancer or colon cancer metastatic to sites other than the liver. Therefore, studies were reviewed for the use in colon cancer metastatic to the liver. Case series were not part of this review.
Currently, surgical excision is the primary modality recommended by consensus guidelines for resectable disease with or without concomitant radiotherapy and chemotherapy. For patients who are not candidates for complete surgical resection, ablative techniques have been described such as radiofrequency, microwave, targeted acoustic waves and electroporation. However, none of the targeted ablation treatments have been effective as a curative treatment approach. In the absence of randomized trials comparing surgical with nonsurgical disease management, surgery has remained the standard treatment approach for patients with resectable, metastatic CRC when the intent is for cure.3
Amygdalos, et al.4 performed a nonrandomized, retrospective comparison study of 3 tissue ablation modalities in 53 patients who had metastatic CRC disease and found that the overall survival (OS) was lowest in the IRE group which had 12 participants. However, this study failed to reach statistical difference at p=0.248. The mean survival was 32 vs. 39 months vs. 52 months for IRE, radiofrequency ablation (RFA) and microwave ablation (MWA).
Hitpass, et al.5 used IRE to treat 23 patients with metastatic CRC to the liver and who had recurred after a prior surgical excision. The study noted that only 5/22 patients were intrahepatic tumor free at 12 months as most patients had progressive disease. In addition, one patient progressed despite treatment and was excluded from the analysis. Furthermore, the retrospective study included heterogeneity in tumor size, tumor biology, patient population and operative experience of the provider.
Frühling, et al.6 performed a retrospective, cohort study of 87 patients with either metastatic hepatocellular carcinoma (HCC) or metastatic CRC. There was no stratification by tumor size, heterogeneity, age of patient, prior treatment, so it was not a true comparative study. In addition, there was no comparison to standard treatments such as radiotherapy or surgical resection. However, they treated 206 tumors in 149 patients with IRE. Eighty-seven patients (58.4%) had colorectal cancer liver metastases (CRCLM), and 62 patients (41.6%) had HCC. Median tumor size was 20 mm. Median OS for CRCLM and HCC, were 27.0 months (95% confidence interval (CI): 22.2-31.8 months), and 35.0 months (95% CI: 13.8-56.2 months), respectively. Median follow-up time was 58 months (95% CI: 50.6-65.4). Local ablation success at 6 and 12 months for HCC was 58.3% and 40.3%, and for CRCLM 37.7% and 25.4%. The median time to local tumor progression (LTP) for HCC was 21.0 months (95% CI: 9.5-32.5 months), and for CRCLM 6.0 months (95% CI: 4.5-7.5 months). At 30-day follow-up, 15.4% (n = 23) of patients suffered from a complication rated as Clavien-Dindo grade 1-3a. Three patients (2.0%) had grade 3b-5 with one death due to a thromboembolic event. It does appear from the study that IRE resulted in a lower success rate at local control for colon cancer metastatic to the liver than primary HCC.
Finally, Meijernik, et al.7 completed a phase II, two-center single arm trial involving a prospective cohort study of 51 patients. A total of 51 participants (median age, 67 years [interquartile range (IQR), 62–75 years]; 37 men) underwent IRE. Of these 51 participants, 50 with a total of 76 colorectal liver metastases (CRLMs) (median tumor size, 2.2 cm; range, 0.5–5.4 cm) were successfully treated in 62 procedures; in one participant, treatment was stopped prematurely because of pulse-induced cardiac arrhythmia. With a per-participant 1-year LTP-free survival of 68% (95% CI: 59, 84) according to competing risk analysis, the primary end point was met. Local control following repeat procedures was achieved in 74% of participants (37 of 50). Median OS from first IRE was 2.7 years (95% CI: 1.6, 3.8). Twenty-three participants experienced a total of 34 adverse events (AEs) in 25 of the 62 procedures (overall complication rate, 40%). One participant (2%), who had an infected biloma after IRE, died fewer than 90 days after the procedure (grade 5 AE). However, the overall complication rate was high at 23/51 patients or 40%. Repeat procedures were frequently required in 37 of the 52 patients. Twenty-five patients required additional systemic regimens for disease progression. Some of the pitfalls of the study include LTP control was only measured at 1 year and was 79%. Most patients with CRC to the liver will progress with their disease. In the study the OS rate was 2.7 years, and this rate was not improved over other modalities of treatment. Their results are in line with those of recent retrospective series. Thus, the authors believe that IRE should be accepted as a niche indication for difficult-to-reach CRLMs, but only in the salvage setting of permanent unresectability and unsuitability for thermal ablation.
The limitations of the studies noted above are that they are all retrospective in nature with limited numbers of patients. In addition, there is no comparison to surgical treatments and there is marked heterogeneity in tumor size and patient characteristics as well as prior treatments. Also, there is a high rate of complications associated with treatment and there is no data to support it being more effective or as effective as standard of care treatments. In all the studies reviewed, adjuvant therapy was utilized after or during treatment and thus the specificity or effect of treatment itself is minimized when treating metastatic CRC to the liver.
Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) has a 5-year survival rate of 10%. Approximately 50% of patients present with metastatic disease and 15% of patients present with anatomically resectable disease. The remaining third of patients are found to have anatomically locally advanced pancreatic cancer (LAPC), as defined by consensus guidelines.8
Currently, the standard of care for such patients includes multiagent chemotherapy with or without radiotherapy, and approximately 20%–30% of patients eventually undergo pancreatectomy. For patients who are not candidates for surgery, several ablative strategies including radiofrequency, microwave, and cryoablation have been investigated for local disease control in unresectable PDAC patients.
Sugumar, et al.9 performed a systematic review (SR) and meta-analysis comparing survival outcomes of multimodal therapy with or without IRE. Of 585 published articles, 48 met inclusion criteria for IRE (n = 27) and without IRE (n = 21) with data for 1420 (IRE) and 1348 (without IRE) patients. The 6/12/24 months OS with IRE was 99%/84%/28%. The 6/12/24 months OS without IRE was 99%/80%/12%. At 12 months from IRE, OS was 55% and progression free survival (PFS) was 12%. The mean major complication and 90-day mortality rates for IRE were 17.95% and 2.65%. The authors concluded that multimodal therapy alone is associated with similar OS to multimodal therapy + IRE in patients with LAPC. Most patients progress and nearly half die within 1 year of the IRE procedure. Given the lack of quality prospective data, IRE should remain experimental and be used with caution in LAPC. GRADE certainty of evidence score of this meta-analysis very low, given the observational design of most studies.
Another meta-analysis looked at complications of IRE in 19 studies,10 involving 954 patients with LAPC. The median age ranged from 53 to 66.5 years old; tumor size ranged from 2 to 8.9 cm. 34.9% (343 of 984) of patients received IRE percutaneously, 65.1% (641 of 984) received IRE through laparotomy. The median follow-up time ranged from 4 to 16.3 months. The probability of IRE-related major (grade 3–5) complications rate was 17% (95% CI: 10–28%). Two deaths related to IRE procedure were reported. The median OS time since IRE ranged from 6.1 to 27 months. This analysis was limited by heterogeneity of patients and treatments.
Ratnayke, et al.11 conducted a SR looking at margin accentuation (MA) IRE in stage III cancer. Nine studies with 235 locally advanced (82%, 192/235) or borderline resectable pancreatic cancer (BRPC) (18%, 43/235) patients undergoing MA IRE pancreatic resection were included. Local and systematic recurrences were noted in 8 and 43 patients, respectively. The weighted-mean PFS was 11 months (95% CI: 7–15). The weighted-mean OS was 22 months (95% CI: 20–23 months) and 8 months (95% CI: 1–32 months) for MA IRE and IRE alone, respectively. The postoperative morbidity was acceptable (30%), albeit with a high postoperative mortality (8%). The review is composed mainly from non-randomized, retrospective, low powered, and observational datasets thereby limiting the comparability of included cohorts. Power limitations further restricted the ability to investigate the relative impact of MA IRE in LAPC vs. BRPC and were therefore combined in the outcome assessments. Furthermore, there remains no standardized indication for MA IRE in pancreatic cancer surgery and so intracohort variances in tumor stage and management do exist. Outcomes are further confounded by the lack of sufficient reporting on adjuvant therapy regimens following resection. Overall, this early non-randomized data suggest MA IRE during pancreatic surgery for stage III pancreatic cancer may result in increased resection rates and improved OS with acceptable postoperative morbidity.
A SR was performed by Moris, et al.12 to collect, analyze, and critically evaluate the role of IRE in LAPC. IRE for LAPC was feasible and safe; however, it was associated with morbidity in approximately 1 in 3 patients, some of whom experienced serious complications, particularly after surgical IRE. In addition, while mortality following IRE was uncommon, it did occur in 2% of patients. While some studies suggested a survival benefit, others failed to note an improvement in long-term outcomes following IRE compared with other therapies.
Tian, et al.13 also looked at a total of 15 eligible articles involving 535 patients. The primary outcomes showed that the pooled prevalence estimates of OS were 94.1% (95% CI: 90.7–97.5), 80.9% (95% CI: 72.5–89.4), 54.5% (95% CI: 38.3–70.6), and 33.8% (95% CI: 14.2–53.5) at 3, 6, 12, and 24 months, and the pooled prevalence data of complete response (CR) at 2 months, partial response (PR) at 3 months, and progression at 3 months were 12.5% (95% CI: 2.9–22.2), 48.5% (95% CI: 39.4–57.6), and 19.7% (95% CI: 7.3–32.2), respectively. The secondary outcomes showed that the pooled prevalence values of post-IRE complications were abscess 6.6% (95% CI: 0.2–13), fistula 10.6% (95% CI: 2.5–18.7), pain 33.5% (95% CI: 14.5–52.5), infection 16.1% (95% CI: 3.9–28.4), thrombosis 4.9% (95% CI: 1.2–8.5), pancreatitis 7.2% (95% CI: 3.1–11.2), bleeding 4.2% (95% CI: −0.5–8.9), cholangitis 4.2% (95% CI: −0.5–8.9), nausea 9.6% (95% CI: 4.4–14.8), biliary obstruction 13.8% (95% CI: 4.2–23.3), chest tightness 7.6% (95% CI: 0.5–14.6), and hypoglycemia 5.9% (95% CI: −0.4–12.2). This meta-analysis indicated that IRE may be safe and effective in prolonging survival for patients with pancreatic cancers. More pairwise-comparison studies estimating IRE against traditional surgical resection and interventional therapies will be needed to identify that clinical benefits are available.
One randomized control trial (RCT) was conducted by Timmer, et al.14 as part of the CROSSFIRE study in Amsterdam. CROSSFIRE was an open-label, randomized phase 2 superiority trial conducted at the Amsterdam University Medical Centre (Amsterdam, Netherlands). Eligible patients were aged 18 years or older with confirmed histological and radiological stage III LAPC. The maximum tumor diameter was 5 cm and patients had to be pretreated with 3 to 8 cycles of FOLFIRINOX. Patients were randomly assigned (1:1) to magnetic resonance imaging (MRI)-guided stereotactic ablative body radiotherapy (SABR) (5 fractions of 8 Gy delivered on non-consecutive days) or CT-guided percutaneous IRE using a computer-generated variable block randomization model. The primary endpoint was OS from randomization, assessed in the intention-to-treat population. Safety was assessed in the per-protocol population. Sixty-eight patients were in this industry sponsored research.
Of the 68 participants, 36 (53%) were male and 32 (47%) were female, with a median age of 65 years (IQR 57-70). Median OS from randomization was 16.1 months (95% CI 12.1-19.4) in the SABR group vs. 12.5 months (10.9-17.0) in the IRE group (hazard ratio [HR] 1.39 [95% CI 0.84-2.30]; p=0.21). The conditional probability to demonstrate superiority of either technique was 0.13; patient accrual was therefore stopped early for futility. Twenty (63%) of 32 patients in the SABR group vs. 19 (59%) of 32 patients in the IRE group had AEs (p=0.8) and 5 (16%) patients in the SABR group vs. 8 (25%) in the IRE group had grade 3-5 AEs (p=0.35). The most common grade 3-4 AEs were cholangitis (2 [6%] in the SABR group vs. 1 [3%] in the IRE group), abdominal pain (1 [3%] vs. 2 [6%]), and pancreatitis (none vs. 2 [6%]). One (3%) patient in the SABR group and one (3%) in the IRE group died from a treatment-related AE.
From this study, CROSSFIRE did not identify a difference in OS or incidence of AEs between MRI-guided SABR and CT-guided percutaneous IRE after FOLFIRINOX. Future studies should further assess the added value of local ablative treatment over chemotherapy alone.
Evidence from 5 SRs of very-low-quality studies and 1 small RCT does not permit conclusions about how well IRE works to treat pancreatic cancer. There is too high a risk of bias to permit conclusions about IRE’s risks and benefits for treating pancreatic cancer. The RCT is at risk of bias due to small sample size and single center focus. One SR (Sugumar, et al.) reported comparative data derived by pooling outcome rates from different sets of studies for each treatment, which is an indirect approach of limited validity. Also, the studies involved different chemotherapy and radiotherapy regimens, which may bias comparison findings. Two other SRs (Tian, et al. and Ratnayake, et al.) did not report comparative data. The SR by Ratnayake, et al. evaluated a more specific patient population (stage III LAPC); therefore, its findings may not generalize to patients with early-stage tumors. Furthermore, Ratnayake, et al. combined IRE with pancreatoduodenectomy in 51% of patients, which may have confounded findings. Another SR (Moris, et al.) was comparative and provided CIs; however, like the other 4, Moris, et al. included no RCTs.
Whether IRE improves patient outcomes when used as an alternative to other ablation techniques or an adjunct to radiotherapy and chemotherapy cannot be determined from comparison studies that provide very-low-quality comparative data. Overall, the studies reported significant rates of treatment-related complications.
Liver Cancer
For solitary primary liver tumors without vascular invasion, surgical resection or liver transplant are considered first-line treatments. For unresectable tumors, liver transplant is preferred, but locoregional therapy can be used as bridge to transplant or as first-line treatment for patients who are not candidates for transplantation. Locoregional therapy is not generally considered an option for patients with metastases but is often used to alleviate symptoms (e.g., biliary obstruction) and with curative intent in select patients with solitary metastases and low recurrence probability. Locoregional therapy options include ablation, transarterial embolization, and external beam radiation therapy (EBRT). Ablation techniques include thermal ablation (RFA or MWA), cryoablation, and IRE. Ablation is considered effective in tumors fewer than 3 cm in diameter and located away from major bile ducts or vessels; however, no consensus exists on which type of ablation is most effective for liver tumors.
Yu, et al.15 published a SR and meta-analysis of IRE in patients with HCC. Twenty-six studies were identified covering 807 participants and 1115 lesions. The complete ablation rate of liver cancer by IRE was 86% (95% CI: 81%-90%). The incidence of IRE-related complications was 23% (95% CI: 17%-28%), but most of them were minor, major complications such as biliary fistula, intestinal fistula and massive hemorrhage were rare. Meta-analysis showed that IRE ablation is safe and effective for liver cancer treatment. Bile duct, intestine and blood vessels adjacent to the tumors are rarely damaged by IRE ablation.
Gupta, et al.16 performed a similar SR and meta-analysis. A total of 25 studies (n = 776, 15 prospective, 10 retrospective) were included. Metastasis, HCC, and cholangiocarcinoma were present in 354, 285, and 100 patients, respectively. The pooled OS at 6, 12, 24, and 36 months was 93.28% (95% CI: 63.23-99.12, I2= 67%), 81.29% (95% CI: 69.80-89.22, I2 = 73%), 61.47% (95% CI: 52.81-69.46, I2 = 0%), and 40.88% (95% CI: 28.43-54.61, I2 = 64%), respectively. The pooled PFS at 6, 12, and 24 months was 79.72% (95% CI: 67.88-87.97, I2 = 70%), 64.19% (95% CI: 56.68-71.06, I2 = 57%), 49.05% (95% CI: 11.47-87.73, I2 = 96%), respectively. Overall complication rate was 23.7%. Major complications (grade C-F) occurred in 6.9% patients. The authors felt that IRE is associated with favorable OS and PFS. Although the overall complication rate is high, most complications are graded as minor.
Zhang, et al.17 performed a multicenter, randomized, parallel-arm, non-inferiority to evaluate the safety and efficacy of an IRE-based device compared to regular RFA of solid liver tumors. One hundred fifty-two patients with malignant liver tumors were randomized into IRE (n = 78) and RFA (n = 74) groups. The primary endpoint was the success rate of tumor ablation; the secondary endpoints included the tumor ablation time, complications, tumor recurrence rates and treatment-related AEs. The success rate of tumor ablation using IRE was 94.9% and was non-inferior to the RFA group (96.0%) (P = 0.761). For the secondary endpoints, the average ablation time was 34.29 ± 30.38 min for the IRE group, which was significantly longer than for the RFA group (19.91 ± 16.08 min). The incidences of postoperative complications after 1 week (P = 1.000), 1 month (P = 0.610) and 3 months (P = 0.490) were not significantly different between the 2 groups. The recurrence rates of liver tumor at 1, 3 and 6 months after ablation were 0 (0.0%), 10 (13.9%) and 10 (13.3%) in the IRE group and 2.9%, 7.3% and 19.7% in the RFA control group respectively. For safety assessments, 51 patients experienced 191 AEs (65.4%) in the IRE group, which was not different from the RFA group (73.0%, 54/184) (P = 0.646). In 7 IRE patients, 8 treatment-related AEs (7.9%) occurred, the most common being edema of the limbs (mild grade) and fever (severe grade), while no treatment-related AEs occurred in the RFA group. The authors concluded that IRE was non inferior to RFA in the treatment of solid liver tumors.
Wada, et al.18 investigated the therapeutic outcomes of 3 different ablation modalities in the treatment of early-stage HCC. A total of 322 consecutive patients with 366 HCCs (mean tumor size ± standard deviation: 1.7 ± 0.9 cm) who underwent RFA (n = 216, 59.0%), MWA (n = 91, 28.3%), or IRE (n = 15, 4.7%) were included. LTP rates for LTP were compared among the 3 modalities. Propensity score-matched analysis was used to reduce selection bias. A significant difference in 2-year LTP rates between the IRE and RFA groups (IRE, 0.0% vs. RFA, 45.0%; p = 0.005) was found. There was no significant difference in 2-year LTP rates between the IRE and MWA groups (IRE, 0.0% vs. MWA, 25.0%; p = 0.103) as well as between the RFA and MWA groups (RFA, 18.2% vs. MWA, 20.6%; p = 0.586). The authors concluded that IRE provides better local tumor control than RFA as a first-line therapeutic option for small perivascular HCC. However, RFA and MWA offer similar therapeutic and safety outcomes in patients with early-stage HCC. Prospective randomized trials are warranted to establish an evidence basis for ablative modality selection for the treatment of early-stage HCC.
Looking at the long-term efficacy of IRE compared to RFA in HCC, Freeman, et al.19 analyzed a total of 190 HCC ablations (31 IRE and 159 RFA) were identified. After propensity score matching, we compared 25 IRE procedures (76% males, median age 62.4 years, median tumor size 20 mm) to 96 RFA procedures (84.4% males, median age 64.3 years, median tumor size 18.5 mm). Local recurrence-free survival (LRFS) did not differ between groups, with a 1-, 2- and 5-year LRFS of 80.4% (95% CI: 55.8-92.2), 69.1% (95% CI: 43.3-84.9) and 44.9% (95% CI: 18.9-68.1%), respectively for IRE and 84.8% (95% CI: 75.2-90.9), 71.3% (95% CI: 58.3-81.0) and 52.1% (95% CI: 35.4-66.4%), respectively for RFA (p = 0.63). There were no major procedure-related complications or deaths in either group.
While IRE remains a relatively novel therapy for HCC cases where standard thermal ablation is contraindicated, the LRFS were comparable to that of RFA. The authors felt that IRE should therefore be considered as a treatment option in such cases when available before stage-migration to non-curative therapies such as transarterial chemoembolization (TACE).
Finally, Narayanan, et al.20 conducted a single center retrospective comparison study of post procedure pain of 43 patients with HCC who were treated with IRE or RFA. Twenty-one patients (15 men, 6 women; mean age 61.5 years) who underwent IRE of 29 intrahepatic lesions (mean size 2.20 cm) in 28 IRE sessions with 22 patients (16 men, 6 women; mean age 60.2 years) who underwent RFA of 27 lesions (mean size 3.38 cm) in 25 RFA sessions. Pain was determined by patient-disclosed scores with an 11-point numerical rating scale and 24-hour cumulative hydromorphone use from patient-controlled analgesia pump. There was no significant difference in the cumulative hydromorphone dose (1.54 mg (IRE) vs. 1.24 mg (RFA); P = 0.52) and in the mean pain score (1.96 (IRE) vs. 2.25 (RFA); P = 0.70). In 9 (32.14%) of 28 IRE sessions and 11 (44.0%) of 25 RFA sessions, patients reported no pain. Complications occurred in 3 (10.7%) of 28 IRE treatments and included pneumothorax (n = 1), pleural effusion (n = 1), and bleeding in the form of hemothorax (n = 1); 1 (4%) of 25 RFA treatments included burn. IRE is comparable to RFA in the amount of pain that patients experience, and the amount of pain medication self-administered.
Evidence from 2 SRs with pooled analyses of single-arm studies and case series suggests that IRE works as intended to ablate liver tissue; however, many patients died or experienced progression within 3 years, and the significance of these data cannot be determined without a comparison to standard-of-care control groups. Two additional RCTs and 3 retrospective comparison studies suggest comparable outcomes between IRE and RFA and MWA; however, the studies assessed too few patients per treatment arm to enable conclusions. CIs, when reported, around pooled outcome estimates were very wide, indicating high outcome variability; also, the studies were at high risk of bias due to 1 or more of the following: small patient populations, lack of randomization, single-center focus, or retrospective design. The studies varied in the number of tumors treated per patient, cancer stage, comorbidities, and timing and administration of systemic chemotherapy regimens; therefore, findings may not generalize across studies or to other patient groups. Most studies did not report key patient-oriented outcomes, such as pain, patient satisfaction, and other health-related quality of life measures, which are important treatment goals in patients with incurable disease. Existing data require validation in additional controlled and comparison studies, ideally RCTs, that report on patient-oriented outcomes over the long-term (>3 years).
Prostate Cancer
Prostate cancer management begins with risk stratification to categorize men into low-, intermediate-, and high-risk groups according to expected survival and risk of metastasis. Patients categorized as low risk may opt for active surveillance (i.e., imaging, biopsy, prostate-specific antigen monitoring at various intervals), and patients categorized as intermediate risk may opt for more aggressive treatments with curative intent, including radical prostatectomy (i.e., surgical removal of the prostate gland) or radiation therapy delivered through EBRT or brachytherapy, generally reserved for high-risk patients, according to clinical practice guidelines.
Surgery, EBRT, and brachytherapy have established effectiveness but carry significant complication and side-effect risks. Radical prostatectomy's potential complications include impotence and urinary incontinence. EBRT and brachytherapy are also associated with risk of short- and long-term complications, including impotence, incontinence, and anal fistula. Interest has therefore grown in whole gland or focal prostate ablation using energy-based techniques as minimally or noninvasive alternatives that may avoid these side effects. Energy-based techniques include cryoablation, high-intensity focused ultrasound (HIFU), laser ablation, IRE, and RFA. Therefore, the risk of overtreatment should be considered by clinicians who must distinguish between patients with high-risk prostate cancer (who would benefit from radical treatment) and patients who may be managed more conservatively, such as through active surveillance or emerging focal therapy (FT). The aim of FT is to eradicate clinically significant disease while protecting key genito-urinary structures and function from injury. However, the effectiveness studies comparing FT including IRE with conventional care options are still lacking.21
Tay, et al.22 performed a systemic review of FT comparing cryotherapy, HIFU, and IRE. They described patient inclusion criteria, selection tools, treatment parameters, and surveillance protocols, and pooled OS, cancer-specific survival (CSS), metastasis-free survival (MFS), biochemical progression (BP), biopsy, secondary treatment, sexual, and urinary function outcomes. Composite failure was defined as salvage whole gland ablation, radical treatment, hormonal therapy or transition to watchful waiting. The authors identified 49 unique cohorts of men undergoing FT between 2008 and 2024 (21 cryotherapy, 20 HIFU, and 8 IRE). Median follow-up ranged from 6 to 63 months. Pooled OS was 98.0%, CSS 99.3%, and MFS 98.5%. Pooled BP was 9.4%/year. Biopsy was mandated post-FT within 24 months in 36/49 (73.5%) cohorts, with pooled clinically significant prostate cancer (grade groups (GG) ≥ 2) rates of 22.2% overall, 8.9% infield, and 12.3% outfield. The pooled rate of secondary FT was 5.0%, radical treatment 10.5%, and composite failure 14.1%. Of 35 studies reporting sexual function, 45.7% reported a low, 48.6% moderate, and 5.7% severe impact. For 34 cohorts reporting urinary function, 97.1% reported a low impact. No differences were noted between cryotherapy, HIFU, or IRE in any of the outcomes. The authors noted that FT with any of these modalities was associated with good short-intermediate term oncological outcomes; however, the outcome reporting was heterogenous, not-blinded and was incomplete in many of the studies. Long-term follow-up and standardized reporting were recommended to better define and report outcomes.
Zhang, et al.23 performed a systemic review of patients treated for low-risk prostate cancer utilizing 12 prospective studies and 7 retrospective studies. A total of 1452 patients underwent IRE as the sole primary treatment modality. Results: The in-field clinically significant prostate cancer rate was reported between 0%–15.6% in the repeat biopsy. The retreatment rate was reported from 8% to 36.6%. The 3 years failure-free survival was presented between 90%–96.8%. The post-operative pad-free continence rate ranged between 96.7%–100%. Greater heterogeneity exists considering the change in erectile function. The most common reported complications were urinary tract infection and hematuria. Major complications were rare. However, the review had several critical limitations. First, the heterogeneity of studies precluded an adequate risk of bias assessment and a competent comparison between studies. Five studies recruited low, intermediate and high-risk prostate cancer; other studies only recruited low-intermediate risk patients. Follow-up time was also short in most of the studies. Finally, definitive proof of oncological effectiveness of IRE against standard of care or other FT modalities is still pending. Solid prospective comparative studies using standardized tools are needed to evaluate the impact of IRE on patients’ long-term survival and quality of life.
Cribbs, et al.24 published a systemic review and meta-analysis which looked at 22 single-arm studies on IRE on 1626 patients with prostate cancer from those studies. However, follow-up was short with 6-12 months and most of the studies were observational and there were no limitations for bias in those studies. Quality of life, outcomes and AEs were similar for patients having treatment with another similar modality, HIFUs. In addition, only 55% of the studies reported biopsy results after treatment for a range of 61% to 100% for a 6-month follow-up period. The observational nature of most studies reviewed and lack of randomized clinical trial-level evidence comparing IRE and HIFU with other prostate cancer treatments limits causal inference. Additionally, heterogeneity in study design, including follow-up time and endpoint definitions, as well as variation in outcomes reported, limited outcome comparisons and risk of bias assessment in both reviews. Selective reporting of oncological and functional outcomes may have also biased results. Due to the investigative nature of IRE and HIFU, most studies included relatively small sample sizes below the Food and Drug Administration (FDA) recommended 100 study participants for studies of prostate cancer ablation.
In a nonrandomized study for early-stage prostate cancer, Scheltema, et al.25 compared 50 patients treated with IRE vs. 50 patients treated with robot-assisted radical proctectomy (RARP). IRE was significantly superior to RARP in preserving pad-free urinary continence (UC) and erections sufficient for intercourse (ESI). The absolute differences were 44, 21, 13, 14% for UC and 32, 46, 27, 22% for ESI at 1.5, 3, 6, and 12 months, respectively. The Expanded Prostate Cancer Index Composite (EPIC) summary scores showed no statistically significant differences. Urinary symptoms were reduced for IRE and RARP patients at 12 months, although IRE patient initially had more complaints. IRE patients experienced more early oncological failure than RARP patients. The authors concluded that long-term oncological data would be required to recommend proof of this FT especially considering early oncological failure with IRE.
George, et al.26 published preliminary results of an initial study for 121 subjects who underwent treatment with IRE using the NanoKnife System in patients with intermediate-risk prostate cancer. Regarding AEs related to IRE, 74 (61.2%) subjects experienced any AE related to IRE and 5 (4.1%) subjects experienced a grade 3 AE related to IRE. However, follow-up data is still being collected and therefore severely limits the ability to have results based upon biopsy-proven efficacy. Second, as a single-arm trial, there is no randomized comparator and all patients received the treatment under study, and therefore only outcomes related to IRE were observed. Lastly, while this study included patients with intermediate-risk prostate cancer, there is heterogeneity even within this subgroup. Therefore, while promising, this study lacks specificity and long-term follow-up to determine whether this modality of FT is effective in patients with prostate cancer.
In a multi-center prospective observational multi-center study, Zhang, et al.27 looked at 411 patients treated from multiple sites with IRE. Data was collected from procedure records and patient questionnaires. However, only 116 of those patients underwent a repeat prostate biopsy at 12-18 months. Among those patients, clinically significant prostate cancer (Gleason ≥ 3 + 4) was detected in 24.1% (28/116) of them; any grade prostate cancers were found in 59.5% (69/116) of the patients. The study also reported initially worse quality of life issues but those gradually improved to baseline; however, the oncological results were consistent with prior studies and did not show improvement over oncological results for other types of prostate surgery.
Consensus guidelines form the American Urological Society noted that whole gland or focal ablation lacks high quality data comparing outcomes to radiation therapy, surgery and active surveillance for intermediate-risk prostate cancer. In addition, their guidelines recommend against whole gland or focal ablation for patients with high-risk prostate cancer outside of a clinical trial.28-30
The limitations of the studies noted above are that they are retrospective in nature or lack randomization including comparison to standard of care, have limited numbers of patients, and lack control of bias. In addition, there is no comparison to standardized surgical treatments and there is marked heterogeneity in tumor size and patient characteristics as well as prior treatments. Also, there is a relatively high rate of AEs associated with treatment and there is no data to support IRE being more effective or as effective as standard of care treatments. In all the studies reviewed, oncological control was limited in duration due to short term follow-up. Finally, there are insufficient urological guidelines to allow this treatment as reasonable and necessary for intermediate or high-grade tumors.
Kidney Cancer
The most common type of kidney cancer is renal cell carcinoma (RCC). Clinicians classify renal cancer clinical progression in 5 stages. Stage T1 kidney cancer is defined as having a tumor ≤7 cm in the kidney only; stage T1a is the subset in which the small renal mass (SRM) is ≤4 cm, and stage T1b is the subset in which the tumor is 4 to 7 cm. Surgery (partial or radical nephrectomy) is the standard treatment for renal cancer. However, thermal ablation therapies have been used as a less invasive, non-surgical treatment option in patients who are contraindicated due to high risk (e.g., tumor in unfavorable anatomic location, older age, renal impairment, serious comorbidities) or in those who wish to avoid surgery. Types of thermal ablation include cryoablation, RFA, and MWA. The National Comprehensive Cancer Network (NCCN) states that thermal ablation (including cryosurgery [i.e., cryoablation]) is an adequate treatment option for early clinical stage T1 renal lesions.
Sorokin, et al.31 conducted a retrospective review of 50 consecutive percutaneous IRE and RFA cases performed from 2013 to 2014. This study only looked at pain and found that patients whose tumors lie close to their body-wall musculature do not have greater narcotic requirements or higher pain scores in the perioperative period after IRE. Percutaneous IRE may be preferred over RFA for SRMs that are close to the body wall to minimize pain.
A very small case series was conducted by Wah, et al.40 of 26 patients with biopsy proven RCC who underwent IRE. The mean tumor size was 2.5 cm, and the median follow-up was 37 months. The primary technical success rate was 73.3%, where 22 RCCs were completely IRE ablated. Seven residual diseases were successfully ablated with cryoablation, achieving an overall technical success rate of 97%. One patient did not have repeat treatment as he died from unexpected stroke at 4-month post-IRE. One patient had Clavien-Dindo-III complication with a proximal ureteric injury. Five patients developed > 25% reduction of estimated glomerular filtration rate (eGFR) immediately post-IRE. All patients have preservation of renal function without the requirement for renal dialysis. The overall 2- and 3-year cancer-specific (CS), local recurrence-free (LRF) and metastasis-free (MF) survival rates are 89%, 96%, 91% and 87%. CT-guided IRE in cT1a RCC is safe with acceptable complications. The primary technical success rate was suboptimal due to the early operator's learning curve, and long-term follow-up is required to validate the IRE oncological durability.
A single-institution retrospective review of cT1a renal masses treated with IRE from April 2013 to December 2019 was performed.32 Those with <1 month follow-up were excluded. IRE was performed with the NanoKnife System (AngioDynamics, Latham, NY). Renal mass biopsy was obtained before or during ablation in most circumstances; biopsy was excluded in some patients because of concern for IRE probe displacement. Post ablation guideline-based surveillance imaging was performed. Initial treatment failure was defined as persistent tumor enhancement on first post-treatment imaging. Survival analysis was performed through the Kaplan-Meier method for effectively treated tumors (SPSS; IBM, Armonk, NY). IRE was used to treat 48 tumors in 47 patients. Twenty-two per 48 tumors (45.8%) were biopsy-confirmed RCC. No complications ≥ Clavien grade III occurred, and 36 patients (76.6%) were discharged the same day. Initial treatment success rate was 91.7% (n = 44/48); 3 treatment failures were managed with salvage RFA and 1 with robotic partial nephrectomy. Median follow-up was 50.4 months (IQR 29.0-65.5). The 5-year LRFS was 81.4% in biopsy-confirmed RCC patients and 81.0% in all patients. Five-year MFS was 93.3% and 97.1%, respectively, and 5-year OS was 92.3% and 90.6%, respectively. Five-year CSS was 100% for both biopsy-confirmed RCC and all patient groups. Conclusions from this study were that IRE has low morbidity, but suboptimal intermediate-term oncologic outcomes compared with conventional thermal ablation techniques for small low-complexity tumors. The authors suggest that use of IRE should be restricted to select cases.
A very small retrospective study of 15 patients33 who underwent IRE were retrospectively reviewed. The success rate of the procedure was 100%. The median tumor size was 2.4 (IQR 1.3-2.9) cm, with a median score of 6 (IQR 5.5-8) per R.E.N.A.L. criteria (radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior, and location relative to polar lines). The patients were followed for 12 months. The author’s conclusion was IRE appears to be a safe and effective treatment for RCC that may offer a tissue-sparing method and complete ablation as an alternative therapy for RCC.
Another tiny (10 patients) feasibility study was a phase 2 trial for IRE for SRMs34 with a mean tumor size of 2.2 cm (range 1.1-3.9 cm). Technical success was 100% The median follow-up was 6 months (range 3-12 months). Mean anesthesia time was 3.7 hours (range 3-5 hours), mean procedural time was 2.1 hours (range 1 hour 45 minutes-2 hours 30 minutes) and mean ablation time was 50 minutes (range 20 minutes-1 hour 45 minutes). The creatinine preoperative and postoperative (1 week, 3 months, 6 months, and 12 months) did not significantly differ. In total, 8 out of 10 cases did not experience postoperative pain.
Liu, et al.35 conducted a retrospective cohort pilot study looking at 5 patients (3 females and 2 males) who presented with a SRM that was deemed not amendable to any other treatment than a radical nephrectomy or IRE. The IRE procedures were carried out by an interventional radiologist in conjunction with a urologist using the AngioDynamics NanoKnife IRE device. Mean tumor size was 28 mm (range 18-39), with a mean R.E.N.A.L. nephrometry score of 8.4±0.55. Over a mean follow up of 22.8 months (range 14-31), 4 out of the 5 patients did not have a radiological recurrence. No AEs were reported after the 5 IRE procedures. Renal function was stable post-IRE, with no to negligible decreases in eGFR detected (range +2 to -13 mL/min/1.73 m2).
Wendler, et al.36 performed a study to assess the efficacy of IRE ablation of pT1a RCC in the first prospective, monocentric phase 2a pilot ablate-and-resect study (Irreversible Electroporation of Kidney Tumors Before Partial Nephrectomy [IRENE] trial). The first 7 study patients with biopsy-proven pT1a RCC (15-39 mm) underwent IRE. Percutaneous CT-guided IRE was performed with electrocardiographic triggering under general anesthesia and deep muscle paralysis with 3-6 monopolar electrodes positioned within the renal tumor. Twenty-eight days later, the tumor region was completely resected to confirm tumor destruction pathologically. There were no major complications. Partial kidney resection was performed in 5 patients, and radical nephrectomy was performed in 2 patients because of central tumor location and ablation areas. Resections revealed by tumor, node, and metastasis classification of the International Union for Cancer Control 2017 no residual tumor as complete ablation in 4 cases (ypT0V0N0Pn0R0) and microscopic residual tumor cells as incomplete ablation in the other 3 cases (ypT1aV0N0Pn0R1). Renal percutaneous IRE appears to be a safe treatment for pT1a RCC but requires substantial procedural effort. Resection specimens of the ablation zone revealed a high rate of microscopic incomplete ablation 4 weeks after IRE. The authors concluded that curative, kidney-sparing ablation of T1a RCC appears possible but needs technical improvement to ensure complete ablation.
Canvasser, et al.37 looked at patients with cT1a renal masses treated with IRE from April 2013 through December 2016 were reviewed. Small, low complexity tumors were generally selected for IRE using the NanoKnife System. A total of 42 tumors in 41 patients underwent IRE. Mean tumor size was 2.0 cm with a median R.E.N.A.L nephrometry score of 5. Twenty-nine patients (71%) were discharged the same day of the procedure, and no major (Clavien grade II or higher) intraoperative or post-operative complications occurred. Initial treatment success rate was 93%; 3 failures (7%) underwent salvage RFA. With a mean follow-up of 22 months, 2-year LRFS was 83% for patients with biopsy confirmed RCC, 87% with biopsy confirmed or a history of RCC, and 92% for the intent-to-treat cohort. The authors concluded that in comparison to extirpation and conventional thermal ablation technologies, IRE has suboptimal short-term local disease control results in this series of small, low complexity tumors. Larger series and longer follow-up will determine the durability of this modality.
Available data are too few and of too low quality to enable conclusions on IRE’s safety and effectiveness for patients with early kidney cancer or how it compares with other treatment modalities. Evidence from 8 small case series suggests IRE is technically feasible for SRMs, but studies reported high rates of complications, including treatment-related events. No studies compared IRE with surgical resection, and whether IRE improves patient outcomes when used as an alternative to other ablation techniques cannot be determined from the 1 small study that compared IRE with RFA. Large, prospective controlled studies are needed to determine IRE’s effectiveness and assess its risk-benefit profile in early kidney cancer.
Furthermore, evidence from 7 small case series suggests SRM ablation with IRE is technically feasible but carries a potentially high risk of recurrence and complications, including treatment-related deaths. One of the 2 largest case series reported an overall complication rate of 24% at median 3-year follow-up. Both case series reported 20% to 60% of patients had postoperative decreased kidney function. One nonrandomized comparison study is at too high a risk of bias due to small size, retrospective design, and single-center focus to enable conclusions about how IRE compares with other ablation techniques or other minimally invasive treatments. This study reported only immediate postoperative outcomes and did not report long-term follow-up. The study did not report on key patient-relevant outcomes, including survival, recurrence, quality of life, and patient satisfaction. Moreover, no studies compared IRE with partial or total nephrectomy, which is the gold standard treatment for SRMs. Comparative studies—ideally RCTs—that compare IRE with other ablation techniques or other minimally invasive procedures that report on relevant outcomes at a longer follow-up (>2 years) are needed.
Breast Cancer
Breast cancer is the most common malignancy among women, where almost 1.7 million new patients worldwide are diagnosed annually. When coupled with early detection, current treatments are highly effective and have contributed to a decline in mortality over the last 3 decades. However, the annual death rate remains unacceptably high. Mortality is typically not associated with breast cancer confined to the breast or draining lymph nodes, rather metastasis to critical organs remains the most significant challenge to patient survival. High-frequency irreversible electroporation (H-FIRE) is a novel tumor ablation technique that utilizes high-frequency bipolar electric pulses to destabilize cancer cell membranes and induce cell death. However, there is currently a paucity of data pertaining to immune system activation following H-FIRE and other electroporation-based tumor ablation technique. Results in animals have demonstrated cell death and inflammation within the tumor.38 Another mouse study found that human breast cancer tumors orthotopically implanted in the mouse mammary fat pad can be successfully treated using IRE delivered by a novel, clinically applicable IRE electrode design. These findings suggest that IRE could be an advantageous alternative to surgical resection for breast conserving therapy.39 At the time of creation of this LCD, there were no peer reviewed published literature for demonstration of IRE safety and efficacy in humans.
