Feasibility of in-office MRI-targeted partial gland cryoablation for prostate cancer: an IDEAL stage 2A study

Introduction

The aim of partial gland ablation for prostate cancer is to eliminate cancer while sparing noncancerous prostate tissue to preserve urinary, sexual and ejaculatory function.1 Interest in prostate gland ablation has grown in the USA due to the recent Food and Drug Administration approval of high-intensity focused ultrasound (HIFU) for prostate tissue ablation and increased use of MRI-ultrasound fusion targeted (MRI-targeted) prostate biopsy, which improves tumour localisation relative to conventional transrectal ultrasound-guided prostate biopsy.1 2 Various thermal energies such as cryoablation, HIFU, laser ablation and short electric pulses have been used for partial gland ablation3 4; however, there is a dearth of comparative outcomes and cost research.

The current post-treatment paradigm of partial gland ablation entails follow-up with active surveillance (prostate specific antigen (PSA), MRI, biopsy). Longitudinal costs of active surveillance have been shown to be more than radical prostatectomy, particularly for younger men with long life expectancy.5 Cryoablation has traditionally been a whole prostate gland treatment under general anaesthesia and is less costly compared with HIFU.2 The ability to perform an office-based procedure would further attenuate expenses from ambulatory surgery centre and general anaesthesia costs while improving patient convenience. In this pilot study, we present our initial experience with in-office, MRI-targeted partial gland cryoablation (PGC) under local anaesthesia.

Materials and methods

Study population

This study included 55 men diagnosed with clinically significant prostate cancer (grade group (GG) ≥2) using targeted biopsy with systematic biopsy at Urological Research Network (n=5; Florida, USA) and NewYork-Presbyterian/Weill Cornell Medicine (n=50; New York, USA). Men were enrolled in clinical trials for PGC (NCT 02381990 and NCT 03492424, respectively). Men were counselled that there was a dearth of long-term cancer control outcomes and comparative studies between PGC and whole gland treatment. Additionally, men were counselled regarding conventional treatment options (surveillance, surgery, radiation). All prostate MRIs were reviewed by an experienced uroradiologist (DJM) to plan PGC, using the Prostate Imaging-Reporting and Data System (PI-RADS) V.2 recommendations. Lesions were graded accordingly6; none had gross evidence of extraprostatic extension or seminal vesicle invasion. The trial flow is demonstrated in figure 1.

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Figure 1

In-office prostate PGC under local anaesthesia trial flow. GG, grade group; PGC, partial gland cryoablation.

Results

Patient characteristics

Median age was 70 years (IQR 63.4–75), median pretreatment PSA was 6.6 ng/mL (IQR 7.7–9.2) and median prostate volume was 39 cc (IQR 31.5–54.5) (table 1, figure 2). Forty-two men (83%) had PI-RADS category ≥4 lesions. Thirty-two (58.2%) men had GG 2, 13 (23.6%) had GG 3, 7 (12.7%) had GG 4 and three (5.5%) had GG 5 on pretreatment biopsy (table 1, figure 2). Two cryoablation probes were used in 38 (69%) men, three probes in 7 (12%) men and 4–6 probes were used for the other subjects. Four men were discharged from clinic without an indwelling catheter because the treatment area was deemed small and away from the urethra.

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Figure 2

Changes in radiographical and pathological features between baseline and post-PGC. Bar graphs showing changes in PI-RADS category (A) and grade group (B) and box and whisker plots showing changes in PSA (C) between baseline and post-PGC. GG, grade group; PGC, partial gland cryoablation; PI-RADS, Prostate Imaging-Reporting and Data System.

Table 1

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Baseline characteristics

Post-treatment outcomes

We observed a 65% median PSA decline, although a quarter of patients had greater than a 94% decrease. The median duration of urethral catheterisation was 6 days (IQR 3–7). The prostate volume decreased by 18.3% on post-treatment MRI. On post-PGC MRI, almost half of men (n=15, 48.4%) did not have an identifiable lesion and nine men (29.1%) had PI-RADS 4 or 5 lesion. Twenty-two men had a benign (42.9%) or GG1 (20.0%) on post-PGC biopsy, whereas, 11 (31.4%) had GG2, 1 (2.9%) had GG3 and another (2.9%) had GG4 (table 2, figure 2). Out of the 13 (37%) men that had recurrence (GG≥2), 7 (54%) were found to have in-field while 6 (46%) had out-of-field recurrences (figure 3A).

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Figure 3

Oncological outcomes and treatment plans following prostate PGC for 35 men. (A) Post-treatment targeted biopsy results. (B) Treatment plan after prostate PGC. GG, grade group; PGC, partial gland cryoablation.

Table 2

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Postpartial gland cryoablation outcomes

Twenty-four (68.6%) men were opted for active surveillance after PGC (two with GG2 and seven with GG1). The rest of the men with GG2 or above on surveillance biopsy underwent repeat PGC (n=5), radical prostatectomy (n=3) or radiation therapy (n=3) (figure 3B). The men who underwent salvage radical prostatectomy had no postoperative complications. Two men had GG2 on both biopsy and prostatectomy specimens while the other man was downgraded from GG4 on biopsy to GG3 at prostatectomy.

There were no significant changes in mean EPIC-CP urinary and sexual function scores from baseline to 4 months (0.71 vs 1.17, p=0.20 and 3.41 vs 4.84, p=0.08, respectively) and from baseline to 9 months (0.71 vs 1.21, p=0.23 and 3.41 vs 3.83 p=0.67, respectively) post-PGC (table 3). No man experienced urinary incontinence.

Table 3

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Baseline, 4 months and 9 months post prostate partial gland cryoablation quality-of-life outcomes

All men completed the procedure successfully. Thirteen men (24%) experienced an adverse event (table 4). In total, there were 22 (40%) CTCAE V.5 score 2 and 5 (9.1%) score 3 events within the first 30 days, although no reported sequelae occurred beyond this interim. There were no severe adverse events (CTCAE grade >3).

Table 4

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Adverse events reported at 30 days after prostate partial gland cryoablation

Discussion

Advances in prostate MRI and targeted biopsy has piqued interest in prostate gland partial ablation.1 2 Additionally, partial gland ablation offers the potential to avoid adverse effects associated with traditional whole-organ therapy, such as urinary incontinence and sexual dysfunction.12 As men are willing to make trade-offs between side effects of treatment and cancer control, prostate gland ablation may preserve health related quality of life and delay definitive therapy.13 However, the Idea, Development, Exploration, Assessment and Long-term study (IDEAL) categorises partial gland ablation at development stage 2A for surgical innovation because comparative outcome evidence is lacking.14

Our pilot IDEAL stage 2A study has several important findings. It is the first to demonstrate that in-office PGC under local anaesthesia is feasible, reproducible and well tolerated. Natarajan et al described the performance of focal laser ablation in a clinic setting under local anaesthesia; however, all subjects had intravenous access for pain medications and sedation administration.4 In the current series, none of the subjects required intravenous sedation and only four (7.3%) needed an oral benzodiazepine for the procedure. Furthermore, there may inherent advantages in performing cryoablation versus, other energy modalities under general anaesthesia. For instance, once the cryoablation probe is activated and ‘stuck’, it remains fixed in place refractory to moderate movement; whereas other energies require complete absence of movement.1 15

Second, we found favourable functional outcomes with no significant change in pretreatment versus post-treatment urinary and sexual function. This is consistent with a multicentre prospective study of 122 men from the UK, who underwent focal cryotherapy for intermediate-risk to high-risk prostate cancer. Similarly, none of the men had urinary incontinence at 3 years, although 16% experienced erectile dysfunction.16 Moreover, our in-office approach for PGC was safe and adverse event evaluation showed 22 CTCAE V.5 score 2 and only five CTCAE V.5 score 3 complications in 55 men. The most common CTCAE V.5 score 2 adverse events were urinary retention and urinary tract infections that were treated with urethral catheter drainage and oral antibiotics, respectively. These adverse events compare favourably to other series. For instance, 6 out of 10 men had a CTCAE V.5 score 2 adverse events after focal laser ablation therapy under local anaesthesia.4 Bass et al reported Clavien-Dindo grade I in 35 (23%) men, grade II in 12 (8%) men and grade III in four (2.6%) out of 153 men that underwent HIFU for localised prostate cancer. Similarly to our series, urinary retention was the most common adverse event (20 men, 13.1%).17 In contrast to HIFU and focal laser ablation, PGC may be monitored with real-time ultrasonography, with 0°C temperatures at the leading edge of the ice-ball.7

The short-term oncological outcomes of in-office PGC were comparable to other partial gland ablation modalities under general anaesthesia. In our series, the recurrence rate was 37% at 6 months. Similarly, Mortezavi et al report a 41% detection rate of clinically significant prostate cancer on 6-month biopsy after HIFU.18 Likewise, Natarajan et al recently reported an in-office, transrectal focal laser ablation experience using Artemis guidance, and described an in-field recurrence rate of 40% with GG 2 or 3 on follow-up 6-month biopsy.4 The difference in in-field recurrence rates between Natarajan et al and our study may be due to the lower radius of laser ablation as compared with cryoablation. Furthermore, all 10 participants in the Natarajan et al study had higher GG disease (GG≥3) compared with our study, where only 23 out of 55 patients (41.8%) had GG≥3. This may also help explain our lower recurrence rates.

We observed that definitive treatment after PGC was feasible and safe. None of the three men who underwent salvage radical prostatectomy experienced complications. All three men required 0–1 pads (EPIC-CP score 0–1) and had erections sufficient for intercourse at 4-month follow-up (EPIC-CP score 0–1). Consistent with our results, a recent systematic review on treatment options after failure of focal therapy showed promising oncological outcomes, and urinary and sexual function outcomes that are not markedly different from those associated with primary treatment.19

Finally, with greater emphasis on value-based care nationally, with value defined as outcomes/costs, we examined resource utilisation and costs of this versus other partial gland ablation approaches. Therefore, we performed TDABC analysis to evaluate in-office PGC under local anaesthesia. We demonstrated that the cost of in-office PGC is almost 50% and 75% of the costs of HIFU and PGC at an ambulatory surgery centre, respectively. The major cost driver of PGC was disposables that comprised more than two-thirds of the total cost. Nevertheless, by eliminating the need for general anaesthesia and/or sedation, we demonstrated that in-office PGC is a cost-effective alternative to ASC PGC and HIFU. In the absence of demonstrating superior outcomes for competing partial gland ablation technologies, the lowest cost approach offers the best value.

Our study must be interpreted in the context of the study design. First, this is a non-comparative study and long-term outcomes are needed to assess cancer control. Because this is an IDEAL 2A study, our focus is on safety and feasibility. Additional follow-up is needed to attain long-term oncological outcomes for in-office PGC. However, our study is noteworthy, as it illustrates that an office-based treatment paradigm for prostate cancer is feasible, particularly in light of greater emphasis on value-based care.2 Second, we used PI-RADS to assess our subjects post-PGC surveillance MRI, despite the fact that PI-RADS was not conceived for post-treatment MRI evaluation. There is currently no framework in place to enable standardised reporting and interpretation of post-PGC surveillance MRI.20 Our recurrence rates are consistent with similar studies. Third, the ability to differentiate between in and out of field recurrences is limited by prostate volume reduction that cannot be clearly delineated with post-treatment MRI.21 Finally, although the TDABC analysis demonstrates the cost-effectiveness of in-office PGC, we did not model costs of complications related to PGC.

In summary, in-office PGC is a promising approach with similar outcomes to ablation under general anaesthesia. However, adherence to biopsy surveillance is critical, as the proper follow-up beyond a clinical trial mandated end of study biopsy is still uncertain.21

Conclusions

We demonstrate that in-office PGC under local anaesthesia is technically feasible and safe for men with localised prostate cancer. In-office PGC demonstrated comparable short-term oncological control and functional outcomes versus HIFU and PGC series performed under general anaesthesia. Despite favourable short-term outcomes, more studies assessing long-term biopsy results are needed before widespread dissemination.