In 1996, a 42-year-old African American man with a prostate-specific antigen (PSA) level of 14 ng/mL (level on repeat testing, 16 ng/mL) was diagnosed with prostate cancer. Pathology reports indicated Gleason score 6 (3+3) adenocarcinoma on the right side of the prostate, in clinical stage T1c. His American Urological Association (AUA) symptom score was reported as 1, and his erectile function score was reported as 3 out of 5 (reported on a 5-point scale, with 1 being no erections and 5 being normal erections without difficulty). He elected treatment with iodine-125 brachytherapy and neoadjuvant hormone suppression. Serial PSA levels showed appropriate response with a PSA nadir <1.0 ng/dL until 10 years after treatment, when he met criteria for biochemical failure. His PSA level was 1.1 ng/mL and results of a bone scan were negative. Transperineal prostate biopsy revealed Gleason score 6 (3+3) cancer in 1 of 16 cores, in the right anterior zone. His AUA score was 7, and his erectile function score was reported as 3 of 5. Salvage, partial-gland prostate cryoablation was offered and applied uneventfully to the right hemigland of the prostate, utilizing a urethral warmer and two freeze-thaw cycles. After cryoablation, no imaging was obtained to formally assess prostate gland treatment.
Two years after cryoablation, his PSA level had continued to rise (3.76 ng/mL) prompting repeat transrectal ultrasound (TRUS) biopsy of the prostate and seminal vesicles, results of which were negative (46 cores). His AUA symptom score was 14, and his erectile function score was reported as 1 of 5. He received dilations for a membranous urethral stricture. Five years after cryoablation, his PSA level was 4.5 ng/mL, and continued to elevate to 10.2 ng/mL, and then to 14 ng/mL. A digital rectal examination revealed an abnormality on the right side of the prostate. A repeat prostate biopsy was performed, revealing Gleason 7 (3+4) prostate cancer in 1 of 12 cores in the right lateral apex of the prostate. He then self-referred to our institution for salvage management options. He reported severe erectile dysfunction (score, 2 of 5) and weak urinary flow, cystoscopically confirmed as resulting from membranous urethral stricture.
Multiparametric magnetic resonance imaging (MRI) of the prostate showed a 17.6-mL prostate with heterogeneous signal changes consistent with prior treatment effect and artifacts from brachytherapy implants. A suspicious region was described as an asymmetric lesion on the right peripheral zone from the middle to the base of the gland (Figure 1). Heterogeneous signal was identified in the seminal vesicles, and the lymph nodes were described as nonsuspicious. The rectal wall was noted to be in close contact with the gland with evidence consistent with fibrosis. A bone scan revealed nothing remarkable.
A full discussion of management options was provided, including a referral to a colorectal surgeon for a discussion of potential surgical risks for rectal wall injury. The patient requested evaluation for candidacy for partial-gland ablation (PGA) therapy with irreversible electroporation (IRE). A confirmatory biopsy of the prostate and seminal vesicles was performed by the transperineal approach (38 cores), identifying Gleason score 7 (3+4) prostate cancer in two of four cores from the right anterior base, with a maximum of 7.7 mm in length and 20% of core involvement. The seminal vesicles were normal.
After the patient was counseled on the potential risks and gave informed consent, he was treated with IRE PGA applied to the right lobe of the prostate using five probes placed under TRUS guidance; a 5-mm clearance from the urethra, rectum, and bladder was utilized to avoid collateral tissue damage. Following cystoscopic evaluation of the urethra and bladder, treatment was applied using 90 pulses per electrode pair. Total voltage delivered between probe sets ranged from 1200 to 2160 V/cm. The procedure lasted 108 minutes. A urethral urinary drainage catheter was left in place for 24 hours after the procedure. The patient was able to urinate upon removal of the catheter.
Three months after IRE PGA, the patient’s serum PSA level was undetectable (<0.05 ng/mL). Results of a traditional TRUS-guided prostate biopsy performed 4 months after treatment was negative for cancer, identifying only fibrosis and focal acute inflammation. Since treatment with IRE PGA, the patient has remained without biochemical recurrence (PSA <0.05 ng/mL) for 3.25 years. PSA levels after therapies are shown in Figure 2.
Four months after treatment, a cystoscopy was performed following the patient’s complaint of having a weakened urinary stream with occasional urinary incontinence. A stricture proximal to the verumontanum of the prostate was identified and treated with resection. After initial improvement, his symptoms recurred and subsequent cystoscopy 12 months following IRE PGA therapy revealed recurrent membranous stricture, which was treated by resection. After 2.7 years without recurrence of stricture disease and persistent urinary incontinence, an artificial urinary sphincter was placed.
Therapeutic options for locally recurrent prostate cancer after primary radiation treatment include hormone therapy, salvage prostatectomy, cryoablation, and high-intensity focused ultrasound. A key factor in treatment selection is the identification of those patients with localized recurrence and lowest likelihood for regionally advanced or metastatic disease. In appropriately selected patients, oncologic control may be reasonably achieved with salvage radical prostatectomy, but the rate of complications, including urinary incontinence, bladder neck strictures, and rectal injury, can be high.1 Salvage cryoablation of the prostate gland has emerged as a less invasive technique with similar effectiveness in local cancer control as salvage radical prostatectomy.2,3 Failure following salvage therapies represents a unique challenge and, for a variety of reasons, the majority of men in this situation find themselves on hormone therapy.
In this case, we report on the use of IRE as a second-line salvage treatment modality in a patient with locally recurrent prostate cancer following primary radiation therapy and one prior ablative procedure. In November 2006, IRE as a modality for soft-tissue ablation received 510(k) clearance from the US Food and Drug Administration using a commercially available direct current pulse-generator device (NanoKnife; AngioDynamics, Latham, New York).4 IRE is an energy-based system that produces tissue ablation by means of short high-voltage electrical pulses that are delivered through metal needle electrodes preplaced within the tissue to be ablated. These pulses create micropores in the cellular membrane of tissues contained within the electrical field, creating a condition of unrecoverable permeability leading to cell death by nonthermal means.5,6 Previous studies in preclinical models of soft tissues, including liver, kidney, and pancreas, have shown ablation effects without damage to surrounding structures in short- and mid-term follow-up.7-11
Few previous studies are available with clinical follow-up of IRE for PGA. A few reports focus on clinical application of this technology in patients.12-14 In 34 patients who underwent primary ablation with IRE to the prostate, complication rates were found to be low, with only grade 1-2 adverse events reported, albeit in patients with anterior treated tumors.13 The development of a grade 3 urethral stricture in our patient may be related to prior treatment, as indicated by his preexisting stricture findings, or due to cumulative vascular damage to periurethral tissue. Rates of urethral stricture after primary and salvage radiotherapy and ablative techniques, including cryotherapy, range from 3% to 15%, dependent on time of follow-up.15-18 As demonstrated by post-treatment contrast MRI studies, the IRE PGA therapy was applied close to the urethra but not circumferentially in order to avoid the risk of profound ischemic involvement. However, this finding also serves to highlight that the “tissue-sparing” properties suggested by studies in normal tissues are neither absolute nor necessarily universal to all tissue types.7,19 Like any surgical intervention, care needs to be exercised when considering use of IRE near sensitive organ sites or in compromised tissues in which damage to these tissues may risk collateral dysfunction.20
Measuring therapeutic outcomes following PGA therapies presents a major challenge, to such an extent that regulatory agencies do not allow the use of IRE or other ablation device technologies to be referred to as a “treatment” for oncologic conditions unless there is demonstrable proof of efficacy. The use of PSA dynamics as an outcome measure is problematic and has not been validated, yet it is a commonly used observatory metric. The study by Valerio and colleagues13 using primary focal IRE for anterior gland ablation reported a roughly 50% decrease in median PSA by 6 months following PGA (6.1 ng/mL preoperatively and 3.2 ng/mL postoperatively). Similar changes have been identified with other modalities that employ hemiablation in the primary setting.14,21,22 In the case presented, the profound change in PSA, we believe, is clinically meaningful due to the long duration of the undetectable PSA level; however, this finding needs to be placed in the context of multiple prior whole-gland therapies. Still, this finding is somewhat unusual, as it is rare to develop undetectable levels of PSA following whole-gland radiation or cryotherapy procedures.2,3,21 In this patient’s procedure, treatment was applied to only half of the prostate gland, and it was expected that PSA would remain detectable due to the untreated remnant of the gland. One possibility includes the formation of an immune response against prostate tissue or PSA generated from multiple therapies applied to this tissue. Such responses following surgical and ablative treatments have been described, although these responses are rare. In this case, we have no evidence to support this speculation with subsequent histology findings demonstrating only nonspecific inflammatory changes and severe fibrosis without viable prostatic glands in the biopsies from the left side of the prostate. Exploration of this hypothesis requires prospective and specific studies. Continued follow-up for this patient will include serial serum PSA testing and further studies, such as prostate biopsy or imaging, considered in the case of biochemical or clinical evidence of recurrence.
It is important to note that this type of response may not be applicable to other patients, but it may hold promise for future trials of IRE in a salvage setting. It is worth noting that we and others have carefully performed IRE for local failure following radiation in selected cases and have not witnessed this form of response in those cases. Further accumulated experience will help to add to the understanding of IRE effects in previously radiated or otherwise ablated tissues, including the effects of serially repeated IRE procedures. Risks for identifiable adverse events such as urethral stricture disease, collateral injury, functional loss, and inflammatory and infectious complications require further evaluation.
This work was supported by The Sidney Kimmel Center for Prostate and Urologic Cancers and the National Institutes of Health/National Cancer Institute Cancer Center Support Grant, award number P30 CA008748.