NanoKnife or irreversible electroporation treatment as a potential focal ablation therapy

Ireversible electroporation (IRE), using the NanoKnife® system, is unique among focal ablation therapies in that it is non-thermal and precise down to the cellular level. There was a very thorough analysis of IRE on this site in 2013, which interested patients are well advised to read. We still do not have enough clinical data to recommend it, but there has been one pilot study with published results.

Valerio et al. reported on 34 prostate cancer patients treated at two institutions (St. Vincent Cancer Centre in Sydney and Princess Grace Hospital in London) between 2011 and 2013. The cohort included low-risk (n = 9), intermediate-risk (n = 24), and high-risk (n = 1) patients. All patients received multiparametric MRI-targeted biopsies in which 20 to 30 cores were taken. Patients were selected who had a single significant focus of cancer:

  • Either predominantly Gleason grade 4
  • Or core length ≥ 4 mm

Patients had to have good performance status, as the procedure involves full anesthesia and complete muscle paralysis.

Acute complications included blood in urine (18 percent), urinary tract infection (15 percent), painful urination (15  percent), and urinary retention (6 percent). All toxicities were low — grade 1 (35 percent) or grade 2 (29 percent) — and were transient. One patient developed tachychardia and had to be watched for a day after the operation.

With a minimum of 6 months follow-up on 24 of the total of 34 patients, all 24 patients were continent and potency was preserved in 19/20 patients (95 percent) who were potent prior to treatment. One of the potential dangers of focal ablation is recto-urethral fistulae, but none have so far been reported for IRE.

With up to 2 years of follow-up with mpMRI among the same 24 patients,

  • 6/24 patients (25 percent) had residual disease.
  • 2/6 patients with residual disease stayed on active surveillance
  • 3/6 patients with residual disease had a second ablation treatment
    • 1 with IRE
    • 2 with high-intensity focused ultrasound (HIFU)
  • 1/6 patients with resideual disease had a radical prostatectomy

As with all forms of focal ablation, residual disease was found in some cases, and multiple treatments may be necessary. With IRE, its sub-millimeter precision is both its greatest strength and its greatest weakness. The strength is in its low risk of harming nearby structures like the bladder neck, urethral sphincter, neurovascular bundles, and rectum. It is also believed to be somewhat sparing of the connective tissue in muscle, blood vessels, and nerves. The weakness is that even with our most accurate mpMRIs, it is impossible to discern microscopic amounts of cancer in the prostate. Even leaving a 5 mm margin around the index lesion, it is impossible to know if it ablated all the cancerous tissue.

Thermal ablation therapies, like HIFU, cryotherapy or laser ablation, are problematic because heat (or cold) dissipates away from the intended treatment zone. That can result in sub-lethal ablation of the intended target while causing thermal injury to nearby organs at risk as well as the neurovascular bundles. Tumors may repopulate in the sub-lethal ablation zone with enhanced vigor. With IRE there is no sub-lethal ablation, and no thermal damage to nearby healthy tissue.

Another issue that applies to all focal therapies is the theory of index tumors. There is a theory that the spread of prostate cancer is from a primary, relatively large, and often higher-grade tumor called an index tumor. According to this theory, all metastases are clones from the original index tumor. If true, ablating the index tumor will stop the cancer. Prostate cancer is known to be multifocal (lots of little tumors) in 80 percent of men, but if the index tumor theory is correct, the multiple tumor foci will not seed any spread — only the index tumor can do that. Liu et al. and Mao et al. showed that metastases arise as clones from a single parent cancer cell, but did not show that the parent cell was in an index tumor. Several studies provide evidence to the contrary:

  • A case report by Haffner et al. (from Johns Hopkins) showed that metastases arose from a small, low grade tumor rather than an index tumor.
  • Cheng et al. found that multiple tumors had independent origins. In 15/18 tumors, this research group found that they arose independently within a single gland, and in 3/18 tumors they arose through intraglandular dissemination from an index lesion.
  • Ibeawuchi et al. showed that there was as much genetic diversity in a unifocal tumor as there were in multifocal tumors.

Clinical evidence for the index tumor theory is based on the fact that a single focal therapy treatment is effective much of the time, at least in the short term. Most likely, it is true in some men but not in others, and it may be true of some, but not all, of the cancers within a single man. The other issue raised by the multi-focal nature of prostate cancer is that the satellite tumors, whether they arise independently or are spawned from the index lesion, may be outside of the treatment range of the focal therapy. Hollmann et al. found that satellite tumors were a median of 1 cm, and up to 4.4 cm, away from the index lesion.

It has not yet been established that immediate focal ablation has any advantage over active surveillance. In men with low-risk prostate cancer, active surveillance is certainly safer. Active surveillance is also, increasingly, being used by men with favorable intermediate-risk prostate cancer. Arguably, there is a window of time during which focal ablation is possible, but we really don’t know that with any certainty. Men who have focal therapy must be closely followed for recurrence because we don’t know whether residual tumors may become active. Focally treated patients are effectively on lifetime active surveillance anyway.

There is obviously much to be learned from clinical trials. There is a second, small-scale, clinical trial (NEAT) that has been completed and should have results soon. NEAT included patient-reported quality-of-life outcomes, and allows for adaptive surgical technique to optimize treatment. The research team treated increasingly larger margins unless toxicity increased. To avoid risk of recto-urethral fistulae, only anterior zone tumors were treated.

There is an on-going, full-scale, clinical trial (NCT01835977) in Amsterdam. They are also running a registry study, and expect to treat 2,000 patients before 2020.

In the US, there are a few practitioners who are experimenting with IRE: Jaime Wong (Jenkins Clinic, Atlanta, GA), Gary Onik (Carnegie Mellon University), and Jonathan Coleman (Memorial Sloan-Kettering Cancer Center) have done over a dozen cases each. There is a pilot trial enrolling just six patients at Duke University (NCT01972867).

Editorial note: This commentary was written for The “New” Prostate Cancer InfoLink by Allen Edel.

2 Responses

  1. To my knowledge, the only technique that has demonstrated to control the damage and get excellent cancer control is brachytherapy. Most interestingly high-dose-rate brachytherapy has the ability to conform the doses of radiation with sub-millimeter accuracy. Brachytherapy is able to do something than none of the other techniques can; this is to treat the whole gland with a low dose of radiation, but increase the dose directed just into the tumor. To me, this seems to be the best strategy available to date.

  2. Dear Dr. Iturriaga:

    I am somewhat puzzled by your comment. As far as I am aware there has been very limited clinical use of either high- or low-dose-rate brachytherapy in the focal treatment of localized prostate cancer to date (although the potential to do this has been known for some time) — see, for example, this article by Tong et al.. Furthermore, I am as sure as I can be that it is not possible to control the delivery of radiation by either high- or low-dose-rate brachytherapy “with sub-millimeter accuracy” because radiation from the source invariably travels over a distance of at least a few millimeters (or more) through prostate tissue.

    It is certainly the case that HDR BT and LDR BT — alone or in combination with external beam radiation therapy — have the potential to treat a wide range of carefully selected patients with localized prostate cancer, but if you are aware of data from any significant series of patients in which HDR BT or LDR BT has been used in hemiablative therapy or the focal therapy of prostate cancer, we would be interested in being made aware of relevant published data.

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