Irreversible Electroporation for Cancer

Title XVIII of the Social Security Act, §1862(a)(1)(A) allows coverage and payment for only those services that are considered to be reasonable and necessary for the diagnosis or treatment of illness or injury or to improve the functioning of a malformed body member

Title XVIII of the Social Security Act, §1862(a)(1)(D) addresses services that are determined to be investigational or experimental

CMS Internet-Only Manual, Pub. 100-02, Medicare Benefit Policy Manual, Chapter 16, §10 General Exclusions from Coverage

CMS Internet-Only Manual, Pub. 100-03, Medicare National Coverage Determinations (NCD) Manual, Chapter 1, Part 4, §270.3 Blood-Derived Products for Chronic Non-Healing Wounds

This is a NON-coverage Local Coverage Determination (LCD) for irreversible electroporation (IRE) as a means of managing cancer except as follows:

Favorable, Intermediate Risk Prostate Cancer, Grade Group 2

Intermediate-risk prostate cancer, Grade Group 2, coverage may be considered reasonable and necessary if all of the following criteria are met:

1. Face to face discussion with the patient regarding risks of treatment with IRE versus other treatment options is documented.
2. Options discussed should include active surveillance, radiation therapy, and radical prostatectomy.
3. Providers should inform patients with intermediate risk prostate cancer considering whole gland or focal ablation that there is a lack of high-quality data comparing ablation outcomes to radiation therapy, surgery and active surveillance.
4. Patients have not been previously treated with IRE.
5. Patient counselling shall include:
   • IRE is not U.S. Food and Drug Administration (FDA) approved or cleared for the treatment of prostate cancer
   • Biopsy-detected cancer after focal therapy (FT) is common within 2 years post-treatment
   • FT or whole gland ablative therapy may impact the safety and/or efficacy of subsequent local therapy
6. Patients considering ablation should be counseled regarding side effects and recurrence risk and should be followed post-ablation with prostate surface antigen (PSA), digital rectal exam (DRE), magnetic resonance imaging (MRI), and biopsy tailored to their specific health and cancer characteristics.

Metastatic Colorectal Cancer to Liver

Metastatic colorectal cancer treatment with IRE to the liver may be considered reasonable and necessary if all of the following criteria are met:

1. Patients that cannot be safely resected or ablated with margins due to proximity to central bile ducts or other structures that cannot be protected, IRE may be considered.
2. Face-to-face discussion with patients regarding risks of treatment with IRE versus other treatment options is documented.
3. Options discussed should include alternative treatment options and medical necessity of IRE over either radiofrequency ablation (RFA) or surgical excision.
4. Providers should inform patients that there is a lack of high-quality data to support this treatment option.
5. Patients should not have had previous failed IRE at the site to be treated as the incidence of higher adverse events (AEs) is unknown.
6. Patient counselling shall include that IRE is not FDA cleared or approved for the treatment of liver cancer.

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, 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, 1 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 1 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 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 (SOC) 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 SOC 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 suggests 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 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 1 (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.

In the PANFIRE II trial,⁴¹ the median survival was not significantly prolonged compared to the group that received prior chemotherapy with gemcitabine-based induction chemotherapy or received FOLFIRINOX. For participants with postresection local recurrence, the median OS was 16 months from diagnosis of recurrence (95% CI: 11 months, 22 months) and 9 months from IRE (95% CI: 2 months, 16 months). After IRE, local recurrence developed in 23 of the 50 participants (46%). Tumor volume of 37 cm³ or greater (HR, 2.9; P = 0.02), pre-IRE carbohydrate antigen 19-9 (CA 19-9) level of 2000 U/mL or greater (HR, 12.1; P = 0.001), and decrease in CA 19-9 level of 50% or less 3 months after IRE (HR, 3.1; P = 0.01) were predictors of worse survival. Fourteen minor and 21 major complications occurred in 29 of the 50 participants (58%). Two participants died less than 90 days after IRE; 1 of these deaths was likely related to IRE. This study does not support improved survival or palliation in patients with advanced pancreatic cancer with high AEs and therefore is not reasonable and necessary.

In the DIRECT Registry study,⁴² the OS was not evaluated, and small sample sizes were used for the comparator being the SOC for chemotherapy alone. The 90-day mortality rates of treatment versus no treatment were the same. Analysis of the DIRECT Registry study has several limitations. First, the AE and survival data are limited to a 90-day period following enrollment. Additional analyses of longer-term outcomes comparing the IRE and SOC treatment groups, including overall and PFS, are planned according to the authors. A multivariate analysis will also be conducted to assess the impact of the differing study variables on observed outcomes. There was also an imbalance in the number of patients enrolled in each arm of the study, with 3 times as many subjects in the IRE treatment arm compared to those treated with SOC. Enrolling patients in a control arm for clinical trials, especially for serious conditions like LAPC, was challenging during the time period for the present study (2019 to 2023). There was patient reluctance since many of the subjects enrolled in the study sought out centers that provided IRE as a treatment. Other patient biases that affected enrollment in the SOC arm included the perception of inferiority of just staying on chemotherapy, the potential toxicity of chemotherapy after 3 months of treatment, and, in some instances, the need for patients to pause chemotherapy. There is also a lack of clear SOC in LAPC after 3 months of disease control and/or response with induction chemotherapy. 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% of 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, they 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.

Cribbs, et al.⁴³ published a meta-analysis comparing IRE with transarterial chemoembolization (TACE). In the 12 IRE publications from a smaller set of patients (195) and 33 TACE publications of 6899 patients the found Median PFS was 10.4 months for IRE and 19–30 months for TACE. Serious AEs (SAEs) were experienced by 4% vs. 5% of IRE and TACE patients, respectively. Most studies were single site (IRE: n=9, 90%; TACE: n=24, 71%) and took place in either Europe or Asia (IRE: n=9, 75%; TACE: n=31, 91%). Comparator treatments were assessed in 2 (17%) IRE studies and 18 (55%) TACE studies. As follow-up periods approached 6 months for TACE, disease recurrence rates began to rise; however, notably, both objective response (OR) and CR increased for IRE at 3 to <6 months follow-up, suggesting a robust, short-term duration of effect. AEs were reported inconsistently across trials and could not be quantitatively analyzed due to variation in measurement and assessment. Additionally, the small overall sample sizes for patients with early-stage HCC and limited or varied reporting on select outcomes, including PFS and AEs, restricted suitability for quantitative analyses. This limits the ability to generalize the results. Small sample sizes for select tumor response meta-analyses, such as IRE stable disease, where minimal events were observed, similarly may limit generalizability of findings. There was significant heterogeneity among the studies that were included in meta-analyses. Given the paucity of PFS data among published studies, further investigation into disease progression after ablative treatment is recommended. The authors concluded that while results are promising, additional research is recommended given the limited data available longer-term and for select outcomes important for the treatment of HCC.

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 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 SOC 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 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 SOC 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 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 patients 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 follow-up to the study published in 2026, George, et al.⁴⁴ published their findings in the PRESERVE Trial. The PRESERVE study is a prospective, nonrandomized trial conducted across 17 U.S. clinical sites. Patients were followed for 12 months. The median age was 67 years (interquartile range [IQR] 61–72), and the median PSA at baseline was 5.8 ng/dl (IQR 4.8–7.9). At 12 months, the primary efficacy endpoint demonstrated that 71% of patients (86/121; 95% CI: 62%, 79%) had a negative in-field biopsy. At 12 months, the rate of any prostate cancer occurrence was 45% (49/110); clinically significant prostate cancer anywhere was observed in 26% (29/110) of patients. The most common AEs (≥10%) included hematuria (44%), erectile dysfunction (18%), dysuria (16%), urinary retention (15%), micturition urgency (14%), pollakiuria (12%), and hematospermia (12%). Four AEs led to study discontinuation: one death (described below) and three instances of prostate cancer risk progression. This single-arm study had several limitations, including the absence of a comparator arm and a lack of central imaging or pathology review, reflecting real-world practice. Additionally, 14 sites performed their first IRE case when the PRESERVE trial started, indicating a potential learning curve. While this study included patients with intermediate-risk prostate cancer, the majority had stage T1c prostate cancer and were found to have Grade Group 2 (GG2).

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.

Skribek, et al.⁴⁵ published in 2025 a systemic review of oncological efficacy and safety of minimally invasive focal and whole-gland interventions for low and intermediate risk prostate cancer. Whole-gland HIFU showed significantly lower recurrence (15%) and postoperative mean PSA levels (0.68 ng/mL) than focal HIFU (24%, 2.81 ng/mL). Recurrence rates were similar for focal vs. extended IRE (30% vs. 26%) and focal vs. whole-gland cryoablation (18% vs. 13%). In-field and out-of-field recurrence rates were similar across treatment modalities (5-15%). Retreatment rates were low, with 6-7% of patients receiving a second ablation and 2-8% progressing to radical or hormonal therapy. Major complications were consistently rare. One-year biochemical recurrence-free survival (BRFS) exceeded 95%, and 5-year BRFS approached 80% for HIFU and cryoablation. They concluded that minimally invasive focal and whole-gland therapies are safe and effective for treating low- and intermediate-risk prostate cancer, with high survival and low major complication rates. Notably, whole-gland HIFU achieves superior biochemical control and lower recurrence than focal HIFU, emphasizing the clinical importance of treatment extent. Complication rates were higher with IRE (37%) and HIFU (29%) compared to cryoablation (21%), though major complications were consistently rare across all modalities. This work is limited by the predominance of retrospective and prospective single arm studies, providing lower levels of evidence, insufficient data on preoperative variables, baseline differences in patient selection (e.g., tumor volume, multifocality, lesion location), physician preferences, operator skills, focus on predominantly short-term outcomes, a generally moderate risk of bias, and the inability to distinguish between low and intermediate-risk cases. Furthermore, the analysis was not based on adjusted, direct head-to-head comparisons, and differences between treatment groups or subgroups may reflect variations in baseline characteristics or study design.

In a salvage study published by Blazeveski, et al.,⁴⁶ the authors published their findings of a prospective FIRE Trial. They looked at 37 patients for salvage FT using IRE after failed radiation therapy. Twenty-eight (75.5%) patients harbored intermediate risk and 9 patients (24.5%) high risk prostate cancer. Local control was achieved in 29 patients (78%) and 27 patients (73%) were clear of local and systemic disease. Four (11%) patients had local recurrence only. Six (16%) patients developed metastatic disease with a median time to metastasis of 8 months. At 12 months post treatment 93% of patients remained continent and erectile function sufficient for intercourse deteriorated from 35% to 15% (4/27). This study lacked a comparator, had a high risk of bias, was not controlled and had small numbers and a high persistence or recurrence of cancer rate with short term follow-up.

In a small SR involving 5 studies, Yilmaz, et al.⁴⁷ looked at IRE after failed definitive radiotherapy. Following IRE, local oncological control was ranging from 67% to 78%. In-field and out-field lesion recurrences after IRE were ranging from 3% to 10% and from 8% to 14%, respectively. Only 1 study reported an overall MFS rate of 91% and a 5-year PFS rate of 60%. The post-IRE continence status ranged 73-100%. Two studies reported a decline in the proportion of patients maintaining erections sufficient for sexual intercourse and 2 studies reported 50% preservation of erection. The majority of complications were of a low-to-mild nature, classified as Clavien-Dindo grade I-II, with the exception of the development of a rectal fistula in a single case. This SR was of low-quality evidence and showed relatively high recurrence rate and deterioration in quality of life including sexual potency and short-term follow-up and was retrospective in nature. The small number of included studies did not compare to radical prostatectomy or other surgical procedures for recurrence of disease.

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

In a large SR published in 2025 by Cheng, et al.,⁴⁸ the authors found wide variation in recurrence rates, potency rates and pad-free rates amongst patients who were treated with IRE. Key findings from their study showed the following: In-field recurrence rates ranged from 0–33% and 0–10% in the primary and salvage settings respectively. Out-of-field recurrence rates ranged from 0–33% and 0–14% respectively. Retreatment rates ranged from 0–37% in the primary setting and 0–24% in the salvage setting. In the primary setting, pad-free rates decreased by 1–2% and 6 studies noted improvements in urinary patient-reported outcome measures (PROMs). Baseline erections sufficient for intercourse declined by 3–22%, and 8 studies reported deteriorations in sexual function PROMs. In the salvage setting, pad-free rates decreased by 4–33%, and potency rates declined by 14-22%. The authors concluded focal IRE is a promising treatment for localized prostate cancer, but evidence regarding its efficacy and safety has been heterogenous amongst existing studies. Longer-term data are required to more definitively assess its efficacy in oncological control, whilst comparative studies are needed to further evaluate its role amongst the growing array of treatment options for localized prostate cancer.

According to the National Comprehensive Cancer Network (NCCN) guidelines, the panel concluded that ablative therapy refers to the use of a device to destroy tissue that can be directed at the part of the prostate gland such as partial gland, hemi-gland, FT or the whole prostate gland. FT includes ablative and non-ablative therapies such as partial prostatectomy and focal radiation therapy. IRE is not currently FDA approved or cleared for the treatment of prostate cancer as a focal or whole gland therapy and should only be used for patients with previously untreated, localized prostate cancer in the context of a clinical trial. Furthermore, the Panel believes that ablative FT should be discouraged in high- or very-high-risk, regional or metastatic prostate cancer outside of a clinical trial. Finally, the Panel concluded that there is insufficient comparative effectiveness evidence for FT to be recommended for patients with intermediate-risk prostate cancer and should only be utilized in the context of a clinical trial. The importance of long-term follow-up is emphasized given the high rates of secondary therapy including recurrence within 2 years of post-treatment.⁴⁹

The limitations of the studies noted above are that they are retrospective in nature or lack randomization including comparison to SOC, 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 SOC 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 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.

While promising, we believe that there is insufficient high-quality evidence to justify the use of IRE for the treatment of any cancer occurrences or metastatic cancerous condition except for within the confines of a well-designed clinical trial or in selective situations as noted below.

In general, this A/B MAC considers IRE for the treatment of cancer, whether primary or adjunctive use, to be experimental and investigational, because its effectiveness has not been established except for very selective situations. IRE is an evolving area of research. This A/B MAC will continue to monitor scientific developments and may adjust this coverage LCD in accordance with emerging evidence.

For prostate cancer, all studies were at high risk of bias due to 2 or more of the following: single-center focus, lack of randomization, retrospective design, small patient populations, and lack of comparison groups. SR authors reported a high degree of heterogeneity across available studies in terms of patient selection, area ablated, follow-up interventions, outcomes measures, and follow-up periods. Additional studies varied in the number of tumors treated per patient, cancer stage, and comorbidities; therefore, findings may not generalize across studies or to other patient groups. Confidence intervals around pooled outcome estimates, when reported, were wide, indicating high outcome variability. No randomized studies directly compared IRE with SOC or alternative ablative techniques (e.g., high-frequency ultrasound, cryoablation, radiotherapy). Existing data require validation in additional controlled and comparison studies, ideally RCTs, in uniform patient populations that report on patient-oriented outcomes over the long-term (≥3 years).

Evidence from 4 SRs with overlapping data from very-low-quality single-arm studies, 1 additional nonrandomized comparison study, and 3 single-arm studies suggests IRE works as intended to ablate prostate tumors without serious adverse events (SAEs) in the short term; however, in the absence of a direct comparison to SOC or alternative ablation techniques, patient-oriented outcomes cannot be interpretated. Larger controlled and comparison studies with long-term follow-up (i.e., up to 5 years) are needed to determine whether IRE improves patient-oriented outcomes, including survival, recurrence, and functional outcomes, compared with SOC (e.g., prostatectomy) or alternative ablation techniques (high-intensity focal ultrasound, cryotherapy).

American Urological Association and ASTRO combined Guidelines:^50,51,52

For patients with favorable intermediate-risk prostate cancer, clinicians should discuss active surveillance, radiation therapy, and radical prostatectomy. (Strong Recommendation; Evidence Level: Grade A)

Clinicians should inform patients with intermediate-risk prostate cancer considering whole gland or focal ablation that there is a lack of high-quality data comparing ablation outcomes to radiation therapy, surgery, and active surveillance. (Expert Opinion)

For patients with unfavorable intermediate- or high-risk prostate cancer and estimated life expectancy greater than 10 years, clinicians should offer a choice between radical prostatectomy or radiation therapy plus androgen deprivation therapy (ADT). (Strong Recommendation; Evidence Level: Grade A)

Clinicians should not recommend whole gland or focal ablation for patients with high-risk prostate cancer outside of a clinical trial. (Expert Opinion)

Therefore, based upon the relative safety of the use of IRE for low risk, intermediate grade prostate cancer, GG2, and minimal AEs reported in this patient population with better reported urine continence and sexual potency, coverage for this specific condition may be reasonable and necessary with proper documentation and after discussion of other treatment options are discussed with the patient.

Consistent with NCCN guidelines for liver cancer, image guided non-thermal ablation (IRE) can be considered in patients that cannot be safely resected or ablated with margins due to proximity to central bile ducts or other structures that cannot be protected.⁵³ However, the overall quality of literature to support the routine use of IRE for liver cancer or metastatic liver cancer is very low and is therefore not reasonable and necessary.

Evidence from 1 nonrandomized comparison study, 3 cohort studies, and 4 case series is too limited in quality and scope to allow conclusions of IRE’s safety and effectiveness for metastatic liver cancer. The studies reported variable survival and frequent local progression after treatment, as well as variable complication rates, ranging from 7% to 40%. The findings are at high risk of bias due to lack of controls, retrospective or single-center study design, and small sample size. 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. None of the studies reported 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 or advanced disease. A high incidence of AEs was also noted when using IRE for metastatic and higher stage liver cancer. In addition, IRE validation requires data from studies comparing IRE with other treatment options; however, only 1 comparative study at high risk of bias is available and assesses too few patients to enable conclusions. Additional studies—ideally randomized controlled trials—that compare IRE with other ablation techniques and other colorectal liver metastases treatments and report on patient-oriented outcomes are needed.

However, in certain situations IRE may be considered as an alternative therapy for patients who cannot be resected or ablated with margins due to proximity to central bile ducts or other structures that cannot be protected since there may be no other viable alternatives and treatment with IRE in this situation may be considered reasonable and necessary.

Hunter DW, Krimsky W, Meyerhoff RR, et al. Pulsed electric field ablation safety and characterization near sensitive structures in lung: A preclinical and clinical case series study. J Thorac Dis. 2025;17(6):3689-3701.

Jimenez M, Flandes J, van der Heijden EHFM, et al. Safety and feasibility of pulsed electric field ablation for early-stage non-small cell lung cancer prior to surgical resection. J Surg Oncol. 2025;131(8):1529-1542.

Knight DB, Hillard H, Handran C, Kuhlman P. Pulsed electric field (PEF) treatment of refractory vulvar melanoma concurrently treated with immune checkpoint blockade demonstrating an abscopal response: A case report. Gynecol Oncol Rep. 2025;57:101671.

Moore WH, Silk M, Bhattacharji P, et al. Early experience with PEF in the setting of recalcitrant stage IV lung cancer. Lung Cancer. 2025.

Moore WH, Silk M, Bhattacharji P, et al. Safety and feasibility of percutaneous pulsed electrical field ablation in multiple organs: A multi-center retrospective study. Eur J Radiol. 2025;187:112078.

Moreno-Gonzalez A, Nafie EHO, Pastori C, et al. Six-month local control rates and immune responses after pulsed electric field ablation in metastatic cancer. Cancers. 2025;17(21):3495.

Pritchett MA, Reisenauer JS, Fernandez-Bussy S, et al. The safety of pulsed electric field ablation before standard of care treatment for patients with metastatic cancer. J Bronchology Interv Pulmonol. 2025;32(4):e01027.

Suh RD, Kim DH, Chiang J, et al. Technical feasibility and safety of image-guided biphasic monopolar pulsed electrical field ablation of metastatic and primary malignancies. J Vasc Interv Radiol. 2024;35(11):1644-1654.

1. Aycock KN, Davalos RV. Irreversible electroporation: Background, theory, and review of recent developments in clinical oncology. Bioelectricity. 2019;1(4):214-234.
2. Davalos RV, Mir LM, Rubinsky B. Tissue ablation with irreversible electroporation. Ann Biomed Eng. 2005;33(2):223-231.
3. Cervantes A, Adam R, Rosello S, et al. Metastatic colorectal cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2023;34(1):10-32.
4. Amygdalos I, Hitpass L, Schmidt F, et al. Survival after combined resection and ablation is not inferior to that after resection alone, in patients with four or more colorectal liver metastases. Langenbecks Arch Surg. 2023;408(1):343.
5. Hitpass L, Distelmaier M, Neumann UP, et al. Recurrent colorectal liver metastases in the liver remnant after major liver surgery-IRE as a salvage local treatment when resection and thermal ablation are unsuitable. Cardiovasc Intervent Radiol. 2022;45(2):182-189.
6. Frühling P, Stillström D, Holmquist F, Nilsson A, Freedman J. Irreversible electroporation of hepatocellular carcinoma and colorectal cancer liver metastases: A nationwide multicenter study with short- and long-term follow-up. Eur J Surg Oncol. 2023;49(11):107046.
7. Meijerink MR, Ruarus AH, Vroomen L, et al. Irreversible electroporation to treat unresectable colorectal liver metastases (COLDFIRE-2): A phase II, two-center, single-arm clinical trial. Radiology. 2021;299(2):470-480.
8. Tempero MA, Arnoletti JP, Behrman SW, et al. Pancreatic adenocarcinoma, version 2.2012: Featured updates to the NCCN Guidelines. J Natl Compr Canc Netw. 2012;10(6):703-713.
9. Sugumar K, Hurtado A, Naik I, et al. Multimodal therapy with or without irreversible electroporation for unresectable locally advanced pancreatic adenocarcinoma: A systematic review and meta-analysis. HPB. 2022;24(5):586-595.
10. Shuiqing H, Sheng L. Is irreversible electroporation (IRE) an effective and safe ablation method for local advanced pancreatic cancer: A meta-analysis. Health Sci Rev. 2022;3:100029.
11. Ratnayake B, Al-Leswas D, Mohammadi-Zaniani G, et al. Margin accentuation irreversible electroporation in stage III pancreatic cancer: A systematic review. Cancers (Basel). 2021;13(13):3212.
12. Moris D, Machairas N, Tsilimigras DI, et al. Systematic review of surgical and percutaneous irreversible electroporation in the treatment of locally advanced pancreatic cancer. Ann Surg Oncol. 2019;26(6):1657-1668.
13. Tian G, Liu X, Zhao Q, Xu D, Jiang T. Irreversible electroporation in patients with pancreatic cancer: How important is the new weapon? Biomed Res Int. 2018;2018:5193067.
14. Timmer FEF, Geboers B, Ruarus AH, et al. MRI-guided stereotactic ablative body radiotherapy versus CT-guided percutaneous irreversible electroporation for locally advanced pancreatic cancer (CROSSFIRE): A single-centre, open-label, randomised phase 2 trial. Lancet Gastroenterol Hepatol. 2024;9(5):448-459.
15. Yu M, Li S. Irreversible electroporation for liver cancer ablation: A meta analysis. Eur J Surg Oncol. 2022;48(6):1321-1330.
16. Gupta P, Maralakunte M, Sagar S, et al. Efficacy and safety of irreversible electroporation for malignant liver tumors: A systematic review and meta-analysis. Eur Radiol. 2021;31(9):6511-6521.
17. Zhang X, Zhang X, Ding X, et al. Novel irreversible electroporation ablation (Nano-knife) versus radiofrequency ablation for the treatment of solid liver tumors: A comparative, randomized, multicenter clinical study. Front Oncol. 2022;12:945123.
18. Wada T, Sugimoto K, Sakamaki K, et al. Comparisons of radiofrequency ablation, microwave ablation, and irreversible electroporation by using propensity score analysis for early stage hepatocellular carcinoma. Cancers (Basel). 2023;15(3):732.
19. Freeman E, Cheung W, Ferdousi S, et al. Irreversible electroporation versus radiofrequency ablation for hepatocellular carcinoma: A single centre propensity-matched comparison. Scand J Gastroenterol. 2021;56(8):942-947.
20. Narayanan G, Froud T, Lo K, et al. Pain analysis in patients with hepatocellular carcinoma: Irreversible electroporation versus radiofrequency ablation—Initial observations. Cardiovasc Intervent Radiol. 2013;36(1):176-182.
21. Pesapane F, Patella F, Fumarola EM, et al. The prostate cancer focal therapy. Gland Surg. 2018;7(2):89-102.
22. Tay KJ, Fong KY, Stabile A, et al. Established focal therapy - HIFU, IRE, or cryotherapy - Where are we now? - A systematic review and meta-analysis. Prostate Cancer Prostatic Dis. 2024.
23. Zhang K, Teoh J, Zhu G, et al. Irreversible electroporation for the focal treatment of prostate cancer: A systematic review. World J Mens Health. 2025;43(2):321-332.
24. Cribbs KA, Manning EF, Zhou J, Lahue BJ, Polascik TJ. Real-world comparative safety and effectiveness of irreversible electroporation and high-intensity focused ultrasound for prostate cancer ablation. Urology. 2023;174:7-17.
25. Scheltema MJ, Chang JI, Böhm M, et al. Pair-matched patient-reported quality of life and early oncological control following focal irreversible electroporation versus robot-assisted radical prostatectomy. World J Urol. 2018;36(9):1383-1389.
26. George AK, Miocinovic R, Patel AR, et al. A description and safety overview of irreversible electroporation for prostate tissue ablation in intermediate-risk prostate cancer patients: Preliminary results from the PRESERVE trial. Cancers (Basel). 2024;16(12):2178.
27. Zhang K, Stricker P, Löhr M, et al. A multi-center international study to evaluate the safety, functional and oncological outcomes of irreversible electroporation for the ablation of prostate cancer. Prostate Cancer Prostatic Dis. 2024;27(3):525-530.
28. Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline, part I: Introduction, risk assessment, staging, and risk-based management. J Urol. 2022;208(1):10-18.
29. Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline, part II: Principles of active surveillance, principles of surgery, and follow-up. J Urol. 2022;208(1):19-25.
30. Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline. Part III: Principles of radiation and future directions. J Urol. 2022;208(1):26-33.
31. Sorokin I, Lay AH, Reddy NK, et al. Pain after percutaneous irreversible electroporation of renal tumors is not dependent on tumor location. J Endourol. 2017;31(8):751-755.
32. Dai JC, Morgan TN, Steinberg RL, et al. Irreversible electroporation for the treatment of small renal masses: 5-year outcomes. J Endourol. 2021;35(11):1586-1592.
33. Wang Z, Lu J, Huang W, et al. A retrospective study of CT-guided percutaneous irreversible electroporation (IRE) ablation: Clinical efficacy and safety. BMC Cancer. 2021;21(1):124.
34. Buijs M, Zondervan PJ, de Bruin DM, et al. Feasibility and safety of irreversible electroporation (IRE) in patients with small renal masses: Results of a prospective study. Urol Oncol. 2019;37(3):183.e1-183.e8.
35. Liu B, Clark J, Domes T, Wall C, Jana K. Percutaneous irreversible electroporation for the treatment of small renal masses: The first Canadian case series. Can Urol Assoc J. 2019;13(9):E263-E267.
36. Wendler JJ, Pech M, Fischbach F, et al. Initial assessment of the efficacy of irreversible electroporation in the focal treatment of localized renal cell carcinoma with delayed-interval kidney tumor resection (irreversible electroporation of kidney tumors before partial nephrectomy [IRENE] trial—An ablate-and-resect pilot study). Urology. 2018;114:224-232.
37. Canvasser NE, Sorokin I, Lay AH, et al. Irreversible electroporation of small renal masses: Suboptimal oncologic efficacy in an early series. World J Urol. 2017;35(10):1549-1555.
38. Ringel-Scaia VM, Beitel-White N, Lorenzo MF, et al. High-frequency irreversible electroporation is an effective tumor ablation strategy that induces immunologic cell death and promotes systemic anti-tumor immunity. EBioMedicine. 2019;44:112-125.
39. Neal RE, Singh R, Hatcher HC, et al. Treatment of breast cancer through the application of irreversible electroporation using a novel minimally invasive single needle electrode. Breast Cancer Res Treat. 2010;123(1):295-301.
40. Wah TM, Lenton J, Smith J, et al. Irreversible electroporation (IRE) in renal cell carcinoma (RCC): A mid-term clinical experience. Eur Radiol. 2021;31(10):7491-7499.
41. Ruarus AH, Vroomen LGPH, Geboers B, et al. Percutaneous irreversible electroporation in locally advanced and recurrent pancreatic cancer (PANFIRE-2): A multicenter, prospective, single-Arm, phase II study. Radiology. 2020;294(1):212-220.
42. Martin RCG II, White RR, Bilimoria MM, et al. Effectiveness and safety of irreversible electroporation when used for the ablation of stage 3 pancreatic adenocarcinoma: Initial results from the DIRECT Registry Study. Cancers. 2024;16(23):3894.
43. Cribbs KA, Baisley WT, Lahue BJ, Peddu P. Clinical and safety outcomes in unresectable, very early and early-stage hepatocellular carcinoma following irreversible electroporation (IRE) and transarterial chemoembolization (TACE): A systematic literature review and meta-analysis. PLoS One. 2025;20(4):e0322113.
44. George AK, Miocinovic R, Patel AR, et al. Irreversible electroporation for prostate tissue ablation in patients with intermediate-risk prostate cancer: Results from the PRESERVE Trial. Eur Urol. 2026;89(1):57-68.
45. Skribek B, Szabó A, Ács J, et al. Oncological efficacy and safety of minimally invasive focal and whole-gland interventions in the treatment of low- and intermediate-risk prostate cancer: A systematic review and meta-analysis. Cancers. 2025;17(17):2863.
46. Blazevski A, Geboers B, Scheltema MJ, et al. Salvage irreversible electroporation for radio-recurrent prostate cancer - The prospective FIRE trial. BJU Int. 2023;131(4):23-31.
47. Yilmaz M, Karaaslan M, Şirin ME, et al. Salvage irreversible electroporation for locally recurrent prostate cancer after definitive radiotherapy: A systematic review. Prostate Cancer Prostatic Dis. 2025;28(3):707-717.
48. Cheng J, Adhami M, King D, Yaxley J, Kavnoudias H, Grummet J. Focal irreversible electroporation for the treatment of localised prostate cancer: A systematic review. Transl Androl Urol. 2025;14(12):4012-4032.
49. National Comprehensive Cancer Network (NCCN). Prostate Cancer (Version 4.2026). Accessed 3/18/26.
50. Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline, part I: Introduction, risk assessment, staging, and risk-based management. J Urol. 2022;208(1):10-18.
51. Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline, part II: Principles of active surveillance, principles of surgery, and follow-up. J Urol. 2022;208(1):19-25.
52. Eastham JA, Auffenberg GB, Barocas DA, et al. Clinically localized prostate cancer: AUA/ASTRO guideline. Part III: Principles of radiation and future directions. J Urol. 2022;208(1):26-33.
53. National Comprehensive Cancer Network (NCCN). Colon Cancer (Version 5.2025). Accessed 3/18/26.

• Irreversible Electroporation
• IRE