Prospective trial of regional (hockey-stick) prostate cryoablation: oncologic and quality of life outcomes

Abstract

Purpose:

To report long term follow-up of the efficacy of subtotal prostate ablation using a “hockey-stick” template, including oncologic control and quality of life (QoL) impact.

Methods:

We performed a prospective controlled trial to evaluate the efficacy of subtotal prostate ablation in selected men with baseline and confirmatory biopsy showing grade group (GG) 1–2 prostate cancer. “Hockey-stick” cryoablation that included the ipsilateral hemi-gland and contralateral anterior prostate was performed. Prostate biopsies and QOL queries were performed at 6, 18 and 36 months following regional ablation, and follow-up was updated to include subsequent clinic visits.

Results:

Between August 2009 and January 2012, 72 men were screened for eligibility and 47 opted to undergo confirmatory biopsy. Of these, 23 were deemed eligible and treated with regional cryoablation. Median age was 64 years. Median follow-up was 74 months. A single patient had <1 mm of in-field viable tumor with therapy effect on 36-month biopsy. At time of last follow-up, a total of 12/23 (52%) patients did not have evidence of disease, all patients had preserved urinary control with no patients requiring pads for urinary incontinence. Sexual decline was significant at 3 and 6 months (P<0.01 for both), though improvement was seen at subsequent time points.

Conclusion:

Subtotal (hockey-stick template) cryoablation of the prostate provides oncologic control to targeted tissue in a generally low-risk group with minimal impact on sexual and urinary function. Further studies are needed to evaluate this ablation template in the MRI-targeted era and higher risk populations.

1. INTRODUCTION:

In patients with low to intermediate risk prostate cancer (PCa), long-term cancer-specific mortality (CSM) rates can be achieved with whole-gland therapy (radical prostatectomy (RP) or radiation therapy (RT)) as evidenced by CSM rates of 7% at 15 years with RP and CSS of 6% at 10 years with RT.¹ However, the negative effects on quality of life (QOL), such as urinary incontinence and sexual dysfunction, are well known.² Active surveillance has been an important strategy designed to monitor select patients with localized PCa for signs of progression, thereby obviating the morbidities associated with traditional radical therapy.³ However, long term rates of metastases are higher in men managed on active surveillance compared to those who undergo up-front radical treatment, even in men with low risk disease.⁴ Furthermore, despite CSM rates for men on AS approximating that of whole gland therapy, many patients suffer anxiety that ultimately drives radical treatment.⁵ A “middle ground” between radical treatment and surveillance has not been firmly established.

Equipoise between radical treatment and observation may be achieved with the use of organ preserving therapies for PCa⁶. With the development of the Index Tumor theory of PCa, in parallel with improved precision with ablative technology, regional ablation of PCa has become an intriguing concept ⁷. Tumor ablation with both thermal and non-thermal sources has gained broad clinical acceptance for the treatment of focal malignancies in selected candidates across wide range of tumor types and tissues.⁸ Prostate cancer has remained an exception. The known multifocality of PCa⁹ has motivated concerns regarding the potential for inadequate oncological control of focal or gland-sparing therapy compared to whole-gland treatments¹⁰. These limitations may be mitigated with the careful application of conformal ablative methodologies that, analogous to the approach for other malignancies, ablate both index tumor and an intended tumor-free margin. Post-RP mapping studies completed by our group suggest that a regional “hockey-stick” ablation field may effectively remove index tumor and other significant disease in over 80% of eligible patients.¹⁰

In the present study, we aim to report oncologic and quality of life (QoL) outcomes, of patients with low and intermediate risk PCa that underwent subtotal prostate ablation (hockey-stick template) in the setting of a single-center clinical trial.

2. PATIENTS AND METHODS:

Patient selection and inclusion criteria

After obtaining institutional review board (IRB) approval, we performed a prospective open-label, controlled trial to evaluate the efficacy of subtotal “hockey stick” prostate ablation in patients with PCa. Between August 2009 and January 2012, men were screened for trial eligibility, defined as having a serum PSA ≤ 10 ng/mL and diagnostic prostate biopsy revealing prostate adenocarcinoma with: 1) <50% of cores from one side of the prostate positive for adenocarcinoma, 2) No greater than 50% tumor core length in any positive core, 3) Gleason grade group (GG) 1 or 2 disease, 4) No GG 4 or 5 tertiary pattern. Patients with contralateral disease were eligible only when the contralateral disease was GG1 and ≤2mm in a single core. Following screening, men were offered study enrollment, which would include a confirmatory biopsy to ensure these eligibility criteria were met. Due to institutional practices at time of study enrollment, prostate MRI was not performed as part of this trial. Screen eligible men underwent confirmatory 12-core, extended scheme biopsy using robotic assistance (TargetScan Transrectal Ultrasound System, Envisioneering Medical Technologies, St. Louis, MO or Artemis Sysetm, Eigen, Grass Valley, CA). To help eliminate longitudinal bias, following 3-D prostate reconstruction, we utilized a robot-assisted 12 core biopsy template targeting the medial and lateral aspects of sextant prostate regions. Final study eligibility was determined based on the above criteria following confirmatory biopsy, during which two cores of the prior area of detected cancer were sampled. Men were excluded who had medical contraindications to treatment, including inability to hold antiplatelet or anticoagulative medications, those that had an AUA symptom score >19, or had signs and symptoms of a urinary tract infection. All patients underwent a pre-procedural bone scan, and detection of metastatic disease precluded enrollment.

Ablation Strategy

We utilized an “anterior hockey-stick” ablation template (Figure A). A dominant hemi-ablation zone ipsilateral to the index lesion was extended anteriorly across the midline to the contralateral gland, preserving the posterior contralateral region of the prostate. This approach was developed due to the high incidence of undetected PCa present within the contralateral side of the prostate and evidence from our group that 83% of men with unilateral-only positive prostate biopsy meeting the enrollment criteria for the current study harbored contralateral disease on final whole-mount pathology following RP¹⁰. This approach additionally leaves 25% of the original prostate intact, with the intention of preserving the contralateral neurovascular bundle to potentially mitigate morbidities associated with whole-gland ablation.

Figure 1: Hockey-stick cryoabloation template and technique.

Panel A depicts the “hockey-stick” template. Panel B shows thermocoupler and probe positioning used to achieve the hockey-stick template. Red text describes temperature probe placement, which is present at the prostatic apex, urethral sphincter, peri-rectal fat, and bilateral neurovascular bundles. Probes 1–6 are placed to provide coverage such that a goal temperature ≤20°C is achieved. Note that probe 3, which is used to provide additional ipsilateral gland coverage, is omitted in cases of smaller glands (as depicted here). They are positioned such that no probe is further than 20mm from a neighboring probe, nor further than 10mm from the prostate capsule, nor closer than 5mm to the urethra or the horizontal prostate mid-line.

Figure B lists details of the hockey stick ablation technique. All procedures involved the placement of a urethral warming catheter with continuous warming at 42°C, real-time monitoring of ice ball formation with transrectal ultrasound, and positioning of four thermocouplers within the dominant treatment zone and contralateral treatment and preservation zones. Two complete freeze-thaw cycles (10 minutes of freezing in each case) were performed with active thawing between cycles 1 and 2, and passive thawing for 10 minutes with the urethral warming catheter in place following cycle 2. All patients received pre-procedural antibiotic prophylaxis and were started on a preoperative oral alpha-blockade for a total of 30 days. Indwelling catheters were placed following the procedure and removed at the treating physician’s discretion (typically 5–10 days).

Post Procedure Follow-Up and Outcomes

All men were evaluated at the 3, 6, 12, 18, 24 and 36 month time points. Each evaluation consisted of a history and physical, serum PSA measurement and QOL measures. The Expanded Prostate Cancer Index Composite (EPIC)¹³ and International Index of Erectile Function Questionnaire (IIEF5)¹⁴ questionnaires were used to evaluate QOL domains. Robotic assisted prostate biopsy was performed in a similar fashion to pre-treatment confirmatory biopsy at 6, 18 and 36 months following regional ablation. Adverse events were collected and reported through the 36 month time point.

The primary study outcome was freedom from treatment failure at 6 month biopsy following focal cryoablation. Two definitions of treatment failure were included. “In-field failure” was the identification of any cancer within the dominant treatment zone. “Out of field failure” was the identification of clinically significant PCa outside of the treatment zone or increase in size of biopsy-proven, untreated contralateral GG1 disease, initiation of secondary PCa treatment, radiologic evidence of metastases, PSA doubling time <10months (during subsequent follow-up), or death from prostate cancer. Secondary outcomes included treatment failure at 18 and 36 months. Other outcomes included PSA response, QOL data at evaluable time points, and presence of adverse events.

Statistical Considerations

For the primary outcome of freedom from treatment failure at 6 months, based on expected enrollment and subsequent treatment of 30 patients we had a power of 0.79 to detect a 6 month treatment failure rate of 20% using a two-sided alpha of 0.09.

3. RESULTS:

Patient characteristics

Between August 2009 and January 2012, 72 men were screened for trial eligibility and 47 chose to undergo confirmatory biopsy. Of these, 23 had confirmatory biopsy parameters consistent with inclusion criteria and proceeded with regional cryoablation on the study protocol. Baseline patient characteristics are seen in Supplementary Table 1. Median age was 64 years (range 56–68 years) and average PSA was 3.9 ng/mL (SD 2.1). Median prostate volume at the time of diagnosis was 30 mL (min: 29 mL; max: 103 mL). In total, 18/23 patients (78.3%) had Gleason GG 1 disease on baseline or confirmatory biopsy and 13 (56.5%) had a single core positive on confirmatory biopsy (or baseline biopsy if confirmatory was negative).

Peri-operative management and adverse events

Foley catheterization was used in all patient undergoing treatment. Median catheterization time was 8 days (min; 5 – max; 42). There was 1 (4%) Clavien grade III adverse event in a patient who required suprapubic tube placement postoperatively due to urinary retention and difficult Foley placement. There were 2 (9%) grade II adverse events. Specifically, 2 patients required catheter re-insertion due to a failed voiding trial.

Oncological outcomes

Among 23 treated patients, 21 underwent 6 month biopsy. Of these, 1/21 biopsies (4.8%) had a positive out of field biopsy at 6 months (GG2 disease). A total of 16 patients had a biopsy at 18 months, of whom 3 (16.7%) had a positive out of field biopsy (GG2). Twelve patients then had a biopsy at 36 months, and five (41.7%) were positive. All five were out of field recurrences, with 4/5 being <1mm of GG1 disease and one being two cores of GG3 disease at the apex. Note that 1/5 of these patients had a prior positive biopsy at 18 months. Therefore, among 23 men initially treated with subtotal ablation, 8/23 (34.8%) had a positive out of field biopsy within three years of follow-up. Notably, all positive biopsies were out of field recurrences, only two were GG2 or higher, both of which were managed with repeat cryoablation.

Regarding extended chart-based follow-up, total median follow-up was 74 months. During this time, new out-of field GG1 cancer was discovered on subsequent biopsies in 9 patients. Out of these, 1 patient opted for radiation therapy, 1 patient underwent re-do cryoablation while 7 others continued on active surveillance without subsequent GG increase at the time of last follow-up.

Quality of life outcomes

Supplementary Table 2 lists urinary erectile quality of life measures based on the AUA symptom score (AUAss) and IIEF surveys, respectively. In terms of urinary function, all patients had preserved urinary control with none requiring pads for urinary incontinence beyond 6 months. Patients had a numeric improvement in AUAss at all time points, including a decrease in the median baseline score of 5 (IQR 2.5–7.5) to 3 (IQR 1.5–6.5) at 3 months (P=0.06). In terms of erectile function, median IIEF-based score decreased from 29 (IQR 19.5–30) at baseline to 11 (IQR 6–22) at 3 months (P<0.01). While scores then increased over time, they never reached pre-procedural levels in the cohort, as a whole, and IIEF-based intercourse satisfaction decreased from a median of 13 (out of 15; IQR 11–14) to 8.5 (IQR 5–14) at 6 months. Changes in urinary and erectile function are represented graphically in Supplementary Figure.

4. DISCUSSION:

In this study we demonstrated that “hockey-stick” subtotal prostate ablation is safe, effective at eliminating tumor within the field of ablation, and provides acceptable QOL outcomes in terms of urinary and erectile function. These data add to the growing body of literature suggesting that focal prostate ablation may offer an alternative to radical treatment for localized PCa in select patients.

Our study is consistent with prior results that focal cryotherapy can eliminate low risk, low volume disease prostate cancer. A study by Barqawi et al. used focal cryotherapy to treat areas of biopsy positivity using similar criteria as those in our study, though ultrasound-guided 3-dimensional mapping biopsy, consisting of 32–64 cores, was used. All patients received a 12 month mapping biopsy, with 81% reported as negative.¹⁵ Data from the COLD registry suggest that focal ablation in men with a similar risk profile (74% Gleason GG 1 disease) resulted in a low (3%) rate of biopsy positivity, though only 14% of patients underwent biopsy at follow-up.¹⁶ A number of other studies have investigated focal cryotherapy and used varying definitions of “for-cause” biopsy in predominantly low risk populations, demonstrating similar results. Among published focal cryotherapy trials, post-treatment biopsy rates of 66%¹⁷, 58%¹⁸, 55%¹⁹ and 89.3%¹⁷ biopsy positivity have been observed in in 25%¹⁷, 40%¹⁸, 13.3%¹⁹ and 4%¹⁷ of subjects, respectively. These data are difficult to compare to the present analysis given differences in patient inclusion criteria, focal techniques, and biopsy indication. Nevertheless, the historical performance of focal cryotherapy in these groups is important, given increased emphasis on the expansion of focal therapy to men with intermediate risk disease.²⁰

More recent studies have examined focal therapy oncologic results in populations at increased risk of disease recurrence. In a contemporary 122 patient series of men from the UK who underwent focal cryoablation, over 90% had GG2 or higher disease. While only 17.2% of men had a positive biopsy within three years, “for-cause” biopsy was performed in only 29 men²¹, with 21/29 (72.4%) demonstrating prostate cancer, only 1 of which being Gleason GG1 disease. Studies examining other ablative energies in predominantly intermediate-risk patients have yielded similar results. Bass et al. performed focal high-intensity focused ultrasound (HIFU) in 150 men, in whom 89% harbored Gleason GG 2 disease or higher. Among 87 (52%) who underwent subsequent biospy, 37/87 (42.5%) of men had GG2 or higher disease (GG1 rates were not reported) at an average of 15 months from biopsy.²² A meta-analysis of studies using a range of ablation energies, entry criteria (including varying amounts of intermediate-risk disease), and biopsy indications, found rates of clinically significant PCa at post-treatment biopsy to be 0–13%, with rates of any cancer of 5.1–45.9%.²³ The fact that 34.8% of men in our highly selected, low-risk cohort had tumor on one or multiple protocol-directed follow-up biopsies should give pause to the use of focal ablation techniques that eliminate less tissue than the “hockey-stick” approach in higher risk men.

Improvements in oncologic efficacy of focal prostate cancer ablation techniques are anticipated through the use of advanced imaging, particularly multiparametric resonance imaging (MRI), in guiding patient selection and treatment. The PROMIS study demonstrated that the combination of MRI with targeted biopsy dramatically increased sensitivity for GG2 or higher disease detection compared to ultrasound-guided systematic biopsy, alone.²⁴ Additional data suggest that genes associated with unfavorable PCa prognosis and metastasis are associated with MRI-visibility²⁵ and that improvements in local imaging are not necessarily augmented by more advanced PET-based techniques.²⁶ Greater integration of MR imaging for focal therapy guidance may therefore facilitate targeting and curative success,^,28 and its incorporation into most ongoing focal studies²⁹ is warranted. We would submit, though, that detailed mapping studies incorporating pre-surgical MRI and targeted biopsy results with post-prostatectomy pathology analyses should be used to guide future ablative maps, similar to how these analyses¹⁰ were used to guide the current study in the pre-MRI era.

QOL outcomes demonstrated in this trial are consistent with results published in the literature. Interestingly, durable improvements in urinary function were observed in our cohort, though these data were limited by sample size. The rate of pad-free continence was 100% in our cohort, consistent with published rates of 83–100% in a systematic review of focal therapy using a variety of ablative techniques.²³ In terms of erectile function, significant declines in erectile function scores were demonstrated at all measured time points. At a median follow-up of 26 months, 81.5% of patients evaluated in 11 focal cryotherapy series were potent following treatment, though this only included men who were potent prior to therapy. Our cohort mostly consisted of men with a normal IIEF score prior to therapy, and while IIEF erectile function declines were not statistically significant beyond the 6 month time point, patient counseling for all men desiring focal PCa treatment should continue to include discussions surrounding erectile function decline. This is especially true given the current standard of active surveillance for low risk prostate cancer, which would likely pair safe oncologic monitoring with improved erectile function in comparison to focal treatment in this group.

Overall, our study offers the advantages of strictly controlled entry criteria, performance of an effective, evidence-based¹⁰ subtotal prostate ablation with a low rate of in-field recurrences, and protocol directed follow-up, including biopsies. While demonstrating both oncologic control and acceptable QOL outcomes, our study is primarily limited by its inclusion criteria. Pre-biopsy MRI was not performed in this group, and though a robotic system was used to longitudinally standardize biopsies, no targeted or transperineal biopsies were performed prior to the procedure. Perhaps most importantly, the population was predominantly low risk, with 78.3% of men harboring GG1 disease and 56.5% with 1 or fewer positive cores. Many of these men are currently considered ideal candidates for active surveillance,³ and oncologic outcomes following the application of “hockey-stick” ablation to a more high risk group is not known. However, given data that some men with intermediate risk prostate cancer, particularly those with GG3 disease, may have long-term oncologic benefit from prostate cancer treatment,³⁰ it is critical to determine if focal therapy techniques can provide this benefit in terms of a durable, curative outcome. Further studies are needed to determine if hockey-stick ablation offers oncologic control while maintaining quality of life in men with intermediate or higher risk PCa.

5. CONCLUSIONS:

Subtotal (hockey-stick template) cryoablation of the prostate provides excellent oncologic efficacy to targeted tissue with minimal impact on sexual and urinary function in well selected patients. This feasibility study can be used to justify further investigations into organ preserving prostate cancer ablative techniques using improved imaging and a variety of thermal energy sources.