Irreversible Electroporation for Prostate Cancer: A Promising but Unproven Treatment Option – What Patients Need to Know

Table of Contents

• Key Points
• What Is Focal Therapy and Why Does It Matter?
• Understanding Irreversible Electroporation (IRE)
• Study Methods: How the Research Was Conducted
• Key Findings in Primary Treatment (229-Patient Study)
• Key Findings in Salvage Treatment (FIRE Trial)
• Clinical Implications: What Does This Mean for Patients?
• Limitations of the Current Research
• The Road Ahead: Future Trials and Recommendations
• Frequently Asked Questions
• Source Information

Key Points

• IRE is a focal therapy using electrical pulses to destroy prostate tumors while sparing surrounding tissue.
• In 229 patients followed 5 years, IRE had 7% in-field recurrence but 24% had residual significant cancer outside.
• Salvage IRE after radiation showed 76% of biopsied patients free of significant cancer, but 16% developed metastases.
• Side effects of IRE include low new urinary incontinence but an 18% risk of losing erectile function sufficient for penetration.
• IRE is not standard of care; randomized controlled trials and longer follow-up are needed to prove its effectiveness.

What Is Focal Therapy and Why Does It Matter?

Focal therapy (FT) for prostate cancer, also called partial gland ablation, is a treatment strategy that aims to destroy only the main area of cancer – the “index lesion” – while leaving the rest of the prostate intact. This approach is designed to reduce the side effects of whole-gland treatments, such as urinary incontinence and erectile dysfunction, while still controlling the cancer.

The target of focal therapy is clinically significant prostate cancer, usually defined as International Society of Urological Pathology (ISUP) Grade Group (GG) 2 to 4. Historically, focal therapy was performed using cryotherapy (freezing the tissue) or high-intensity focused ultrasound (HIFU), which heats tissue using ultrasonic waves.

Despite growing interest, focal therapy is not yet an established standard of care for men with intermediate-risk prostate cancer. Its popularity has increased in recent years, largely because of improvements in imaging: multiparametric MRI (mpMRI) and, more recently, prostate-specific membrane antigen PET/CT (PSMA PET/CT) can now better identify and stage the cancer.

Understanding Irreversible Electroporation (IRE)

Irreversible electroporation (IRE) is a newer type of focal therapy. It uses high-voltage electrical pulses delivered through several needle electrodes placed directly into the prostate. These pulses create permanent holes in the cancer cells’ outer membranes, causing them to become leaky, lose their internal balance, and ultimately die.

Early small phase I and II clinical trials suggested that IRE is safe, with few serious side effects. In the short term (biopsies taken within 1 year of treatment), in-field recurrence rates – meaning cancer returning in the treated area – were below 15%. However, those early findings came from studies with relatively short follow-up.

Study Methods: How the Research Was Conducted

This editorial discusses three papers from Australian research teams published in the same issue of the journal BJU International. Together, they provide the largest and longest follow-up data on IRE for prostate cancer to date, both as a first-line (primary) treatment and as a rescue (salvage) treatment after radiation therapy has failed.

The first study, led by Scheltema and colleagues, followed 229 patients with localized prostate cancer who were treated with focal IRE. The median follow-up was 60 months (5 years). A large majority of patients had intermediate-risk disease (86%), and 7% had high-risk disease. Patients underwent periodic mpMRI scans as part of the study protocol, and a transperineal template mapping biopsy was performed 12 months after treatment. The main measure of progression was the initiation of radical treatment – meaning a whole-gland treatment like surgery or radiation – but the exact criteria for deciding when to start such treatment were not specified.

The second and third papers, from Geboers and colleagues and Blazevski and colleagues, focus on the use of IRE in patients with prostate cancer that has returned after radiation therapy (radio-recurrent disease). The prospective FIRE clinical trial (Australian New Zealand Clinical Trials Registry number ACTRN12617000806369) enrolled 37 men with radio-recurrent prostate cancer who were treated with focal IRE. All 37 men had focal Grade Group ≥ 2 disease based on mpMRI and biopsy, and 64% had Grade Group ≥ 3 disease.

Key Findings in Primary Treatment (229-Patient Study)

The 5-year results from the 229-patient study are encouraging in some ways but raise concerns in others.

• Low rate of radical treatment: Only 17% of patients later required radical treatment (surgery or radiation), which was the study’s definition of progression. However, the criteria for starting such treatment were never clearly defined.
• Good biopsy compliance: A total of 82% of patients underwent the planned 12-month post-treatment biopsy.
• Low in-field recurrence: Recurrence inside the treated area was only 7%, similar to earlier IRE studies.
• Residual cancer outside the treated area: Among patients who had a biopsy, 24% had residual clinically significant prostate cancer, and most of these cancers were found outside the treated field (out-of-field). This means that while IRE was effective at killing cancer in the treated area, it did not catch all significant cancers elsewhere in the gland.
• Urinary control was preserved: There was virtually no new urinary incontinence during the study period, consistent with other focal therapy studies.
• Sexual function was affected: However, 18% of men who started the study with erections sufficient for penetration lost that ability during the study.

The authors note that while 5 years of follow-up is longer than in previous IRE studies, it may still be too short. Data from active surveillance studies show that the time to local or distant failure on imaging is often longer than 5 years, even for low- and intermediate-risk disease. In addition, a single biopsy at 12 months may miss many late failures. A recent HIFU study showed that a substantial number of biopsy-defined failures were only detected at the second protocol-mandated biopsy at 24 months after treatment.

Key Findings in Salvage Treatment (FIRE Trial)

Treating prostate cancer that recurs after radiation therapy is difficult. Patients have limited effective options, and the side effects of salvage whole-gland treatments can be severe.

For context, the editorial cites data on salvage radical prostatectomy (surgery to remove the prostate after radiation has failed). Among men undergoing that procedure, the reported 10-year biochemical recurrence (BCR) – a rise in prostate-specific antigen (PSA) indicating cancer persistence – and metastasis-free survival rates are 37% and 77%, respectively. This means that after 10 years, only about 37% of men were free of BCR, and about 77% were free of metastasis. But the cost is high: significant rates of urinary incontinence, erectile dysfunction, and urethral strictures, regardless of whether the surgery is performed open or minimally invasive.

Other salvage options include salvage radiation, androgen-deprivation therapy (ADT), or simply observation until metastasis develops and then starting ADT.

The FIRE trial examined 37 men with radio-recurrent prostate cancer treated with focal IRE. Key results:

• Median follow-up: 29 months.
• Biopsy compliance was low: Only 46% of patients had a biopsy at 12 months after treatment, which raises questions about the reliability of the findings.
• Freedom from significant cancer: Among the men who did undergo biopsy, 76% were free of clinically significant prostate cancer (defined as Grade Group ≥ 2) at that time.
• Imaging results: 29 patients had either a PSMA PET/CT and/or mpMRI; of these, 22 patients (76%) were interpreted as having no evidence of disease.
• Biochemical recurrence: 7 patients had BCR during the study, defined using the Phoenix criteria (a PSA rise above a certain threshold).
• Metastatic disease: 6 patients (16%) developed metastatic disease.

The authors describe these data as encouraging, but far from definitive. They point out that the Phoenix criteria likely underestimate the true rate of BCR because PSA levels after IRE are low to begin with, and the starting PSA before salvage is often low as well. Without routine post-treatment biopsies, it is difficult to know whether the ablations actually changed the natural history of the disease – or whether some patients might have progressed similarly had they simply been observed or treated with whole-gland therapy.

Clinical Implications: What Does This Mean for Patients?

For men considering IRE as a primary treatment, the data suggest that the procedure is reasonably safe and can destroy the targeted tumor in most cases. The low rate of new urinary incontinence is a major plus. But the risk of leaving significant cancer outside the treated area (seen in 24% of biopsied patients) is an important reminder that successful focal therapy depends on accurate imaging and biopsy mapping – and that even with modern tools, some cancers are missed.

For men with radio-recurrent prostate cancer, IRE offers a potential salvage option that may be better tolerated than salvage surgery or radiation. The FIRE trial showed that 76% of biopsied patients were free of significant cancer at 12 months, with relatively low rates of severe complications. However, the low biopsy rate (46%) and the occurrence of metastases in 16% of patients make it clear that IRE is not a guaranteed cure.

The editorial’s authors – led by Dr. Jonathan Fainberg at Memorial Sloan Kettering Cancer Center – stress that these results are encouraging but not conclusive. “The data presented here represent the IRE study with the largest cohort of patients and longest follow-up to date,” they write. But they also caution that 5 years is too short to call IRE oncologically effective, given prostate cancer’s long natural history.

Limitations of the Current Research

The editorial identifies several specific limitations in the studies reviewed:

1. Incomplete biopsy data: In all studies, a portion of men did not undergo the 12-month post-treatment biopsy. This limits the generalizability of the findings because those missing biopsies could have contained important information about recurrence.
2. Inadequate follow-up duration: A median follow-up of 5 years in the primary setting is longer than earlier IRE studies, but still well below the time to local or distant failure seen in active surveillance studies for low- and intermediate-risk disease.
3. Solitary biopsy timing: A single 12-month biopsy may not catch all failures. A recent HIFU study found that many biopsy-defined failures were only picked up on a second biopsy at 24 months.
4. Unclear progression criteria: In the primary study, the criteria for starting radical treatment were never specified, making the 17% progression rate difficult to interpret.
5. Salvage trial limitations: The Phoenix criteria for biochemical recurrence may underestimate true recurrence rates after salvage IRE because PSA nadirs are low. The lack of routine post-treatment biopsy in the salvage trial is particularly concerning.
6. No randomized controlled trials: No randomized trials have yet shown that focal therapy can safely delay the need for radical therapy when compared to active surveillance.

The Road Ahead: Future Trials and Recommendations

The editorial points to a growing pipeline of research. In the United States, the PRESERVE clinical trial (clinicaltrials.gov identifier NCT04972097) is currently enrolling patients with primary prostate cancer to be treated with IRE. That trial will also require mandatory post-treatment biopsy. The authors say they are “waiting for recruitment to close and the data to mature.”

For radio-recurrent disease, the Australian data are encouraging enough to justify launching a clinical trial of salvage focal IRE in the United States, where salvage focal therapy remains poorly studied.

However, the authors are clear that the burden of proof remains for the treatment of primary prostate cancer. “There have been no randomised controlled trials (RCTs) that have shown that FT can safely delay the indications for radical therapy when compared to AS,” they write. They also note that the U.S. Food and Drug Administration has emphasized that mature data from randomized controlled trials will be essential to determine the benefits and risks of focal therapy, and will ultimately determine whether focal therapy has a place as a standard-of-care option for localized prostate cancer.

For patients considering IRE today:

• Discuss with your urologist whether you are a candidate for focal therapy, and ask about your ISUP Grade Group and imaging findings.
• Understand that IRE is not yet a standard of care, and long-term cancer control data are still maturing.
• If you have had radiation and are considering salvage IRE, ask about the likelihood of requiring additional treatment and about the importance of post-treatment biopsies.
• Consider enrolling in clinical trials such as PRESERVE, or asking your doctor about other ongoing research.
• Weigh the trade-offs: IRE may preserve urinary continence better than whole-gland therapy, but it does still carry a risk of erectile dysfunction (18% in the largest primary study), and there is a real chance that significant cancer may remain outside the treated area.

Frequently Asked Questions

What is irreversible electroporation (IRE) for prostate cancer?

IRE is a minimally invasive focal therapy that uses high-voltage electrical pulses delivered through needle electrodes placed directly into the prostate. The pulses create permanent holes in cancer cell membranes, causing the cells to die. Unlike whole-gland treatments, IRE targets only the main tumor, aiming to preserve surrounding healthy tissue and reduce side effects like incontinence and erectile dysfunction.

How well does IRE control cancer in newly diagnosed patients?

In the largest study to date, 229 patients with localized prostate cancer were treated with IRE and followed for a median of 5 years. Recurrence inside the treated area was low at 7%. However, 24% of patients who had a biopsy had residual clinically significant cancer outside the treated area, and 17% later required radical treatment.

What are the side effects of IRE for prostate cancer?

In a 229-patient study, virtually no new urinary incontinence was reported during follow-up. However, 18% of men who initially had erections sufficient for penetration lost that ability during the study. IRE is generally considered safe with few serious side effects, but erectile dysfunction remains a possible risk.

Can IRE be used if radiation therapy has failed?

Yes, a study called the FIRE trial examined 37 men with prostate cancer that recurred after radiation. They were treated with focal IRE. Among those who had a biopsy, 76% were free of clinically significant cancer at 12 months. However, 16% of all patients developed metastases, and biopsy compliance was low at 46%.

Is IRE a proven standard treatment for prostate cancer?

No, IRE is not yet a standard of care. Experts note that follow-up is still too short and no randomized controlled trials have shown that focal therapy can safely delay the need for radical therapy compared to active surveillance. Long-term cancer control data are still maturing, and more research is needed.

What does 24% residual cancer outside the treated area mean for me?

In a study of 229 patients treated with IRE, 24% of those who underwent a biopsy had clinically significant prostate cancer outside the treated area. This means IRE effectively destroys the targeted tumor, but accurate imaging and biopsy mapping are crucial because some cancers can be missed elsewhere in the prostate.

What follow-up is needed after IRE?

After IRE, periodic multiparametric MRI scans and a transperineal template mapping biopsy at 12 months are typically part of the research protocol. However, a single biopsy at 12 months may miss late failures; some HIFU studies found failures only detected on a second biopsy at 24 months. Discuss your follow-up plan with your urologist.

Should I get a second opinion before choosing irreversible electroporation (IRE) for prostate cancer?

Yes, a second opinion is advisable before choosing IRE, as it is not yet a standard treatment. In the largest study, 24% of patients had residual significant cancer outside the treated area, and 18% lost erectile function. For radiation-recurrent cancer, 16% developed metastases. Because long-term outcomes are unproven and randomized trials are lacking, an independent expert can help you weigh IRE against active surveillance or whole-gland therapy, and clarify the need for post-treatment biopsies. Diagnostic Detectives Network provides independent expert second opinions.

Source Information

This patient-friendly article is based on the following peer-reviewed editorial:

Title: “Focal therapy using irreversible electroporation: reported successes, with clear limitations, in both primary and salvage settings”

Author: Jonathan Fainberg, Memorial Sloan Kettering Cancer Center, New York, NY, USA

Journal: BJU International, 2023;131(Supplement 4):34–35. doi:10.1111/bju.16006

The editorial discusses three studies published in the same issue:

• Scheltema MJ, Geboers B, Blazevski A et al. Median 5-year outcomes of primary focal irreversible electroporation for localised prostate cancer. BJU Int 2023. doi:10.1111/bju.15946
• Geboers B, Scheltema MJ, Blazevski A et al. Median 4-year outcomes of salvage irreversible electroporation for localized radio-recurrent prostate cancer. BJU Int 2023. doi:10.1111/bju.15948
• Blazevski A, Geboers B, Scheltema MJ et al. Salvage irreversible electroporation for radio-recurrent prostate cancer – the prospective FIRE trial. BJU Int 2023. doi:10.1111/bju.15947

Note: This article is a translation of an editorial commentary, not a primary research paper. It is provided for educational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional about your individual diagnosis and treatment options.