Partial-gland Cryoablation Outcomes for Localized Prostate Cancer in Patients with Magnetic Resonance Imaging (MRI)-visible and MRI-invisible Lesions

Take Home Message Outcomes after partial gland ablation of magnetic resonance imaging (MRI)-invisible prostate cancer are unknown. We demonstrated that men with MRI-visible and MRI-invisible lesions have similar oncological and functional outcomes and complication rates after cryoablation.


Introduction
Prostate cancer (PCa) is the most commonly diagnosed solid tumor among US men, with estimated incidence of 268 490 and mortality of 34 500 in 2022 [1]. For healthy men with clinically significant PCa (grade group [GG] 2), professional guidelines recommend whole-gland definitive therapy with either radical prostatectomy (RP) or radiation therapy (RT) [2,3]. However, these treatments have negative effects on health-related quality of life (HRQoL) in terms of urinary and sexual function [4]. New treatment options such as partial gland ablation (PGA) have emerged that may attenuate the negative sequelae of whole-gland treatment while achieving cancer control [5]. American Urological Association (AUA) guidelines currently state that PGA may be considered for intermediate-risk PCa, but there is a lack of high-quality evidence comparing ablation to whole-gland treatments [3]. Nevertheless, interest in PGA for PCa has surged in the USA because of an increase in the use of image guidance for targeted prostate biopsy and recent Food and Drug Administration (FDA) approval of high-intensity focused ultrasound (HIFU) for prostate tissue ablation [6,7]. Various modalities, including HIFU, cryoablation, laser ablation, irreversible electroporation, and magnetic resonance-guided focused ultrasound surgery (MRgFUS), are currently used for PGA.
Contemporary expert consensus on PGA recommends treatment of clinically significant PCa (GG 2) diagnosed via targeted biopsy of MRI-visible lesions [8] on the basis of current evidence on PGA for MRI-visible lesions [9][10][11][12][13][14][15]. While multiparametric MRI improves detection of GG 2 PCa, approximately 4-6% of GG 2 PCa cases are MRIinvisible and detected via systematic biopsy alone [16,17]. Treatment outcomes for MRI-invisible PCa have not been reported. Therefore, the primary objective of our study was to compare cancer control outcomes of PGA for treatment of MRI-visible versus MRI-invisible lesions. Secondary outcomes were adverse events and HRQoL. We hypothesized that treatment outcomes after cryoablation for men with MRI-visible and MRI-invisible prostate cancer are similar.

Study population
We assessed men treated with partial-gland cryoablation at New York-

Statistical analysis
Results for continuous variables were reported as the median with interquartile range (IQR

Results
There were no significant differences in demographic characteristics (Table 1) between the MRI-visible PCa (n = 51) and MRI-invisible PCa (n = 16) groups. However, men with MRI-visible cancer had a greater maximum cancer core length on biopsy (7.0 vs 4.0 mm; p = 0.012). In addition, ten men (67%) in the MRI-invisible group had PI-RADS 4 lesions; however, these lesions were not correlated with clinically significant PCa on targeted biopsy and were not treated with cryoablation. The majority of prostate MRI scans were performed internally (70%), and all were reviewed internally by genitourinary radiologists. There were no significant differences between the two groups with regard to treatment laterality, extent, or location. Over median follow-up of 44 mo (IQR 17-54), 23 men (34%) had PCa recurrence at 12 mo and 29 (43%) had recurrence at 24 mo (Table 2). PCa recurrence rates at 12 mo were similar in the MRI-visible and MRI-invisible groups (39% vs 19%; p = 0.2). In-field (43% vs 19%; p = 0.14) and out-of-field (26% vs 19%; p = 0.7) recurrence rates did not differ significantly between the two groups (Supplementary Table 1). Furthermore, in-field and out-of-field surveillance biopsy results and median cancer core lengths did not differ significantly between the groups. Of the ten men in the MRI-invisible group with PI-RADS 4 lesions on pretreatment MRI, two experienced out-of-field recurrences; neither of these recurrences corresponded to the original PI-RADS 4 lesion.
The first surveillance biopsy within 12 mo of treatment was performed in 86% of the MRI-visible cases and 88% of the MRI-invisible cases. PCa GG found on first and second surveillance biopsies did not differ significantly following PGA of MRI-visible vs MRI-invisible lesions ( Table 2). A log-rank survival analysis demonstrated no significant differences between the two groups ( Fig. 2). Recurrence-free survival rates at various times are listed in Supplementary  Table 2.
Of the 35 men with recurrence after PGA overall, eight pursued AS while the rest opted for salvage therapy. There were no significant differences in the choice of salvage therapies between the two groups ( Table 2). Of the six men with pretreatment GG 4-5 PCa, two developed recurrence within 12 mo and one developed recurrence at 47 mo.
Analysis was also performed to compare the group with at least one surveillance biopsy and the group with no surveillance biopsy. There were no significant differences in age, race, PSA, pretreatment biopsy GG, or other baseline characteristics between these subgroups (Supplementary Table 3). The only difference noted was that men with  ( 2 0 2 3 ) 3 8 -4 5 surveillance biopsy had a higher rate of focal treatment than men without follow-up biopsy (96% vs 63%; p = 0.014).
Additional analysis was performed for the 11 men who had salvage cryoablation after initial recurrence. All subjects initially had MRI-visible lesions, and 73% had an initial surveillance biopsy within 12 mo after salvage treatment. The 12-mo recurrence rate after salvage therapy was 44.4%, and one patient developed metastatic disease 32 mo after treatment (Supplementary Table 4).

Functional outcomes
All men with available EPIC-CP data (n = 45) were continent (0-1 pads/d) at baseline and at 12 mo after treatment. Of the 36 men (84%) who were potent at baseline, 16 (76%) remained potent at 12 mo after cryoablation. There were no significant differences between the MRI-visible and MRI-invisible groups with regard to baseline (81% vs 92%; p = 0.7) and 12-mo (77% vs 75%; p = 1) potency rates. In addition, there were no significant differences in median urinary function or sexual function EPIC-CP scores at baseline or at 3 mo and 12 mo after treatment (Table 3).

Adverse events
Twenty-six men (35%) experienced adverse events within 30 d of cryoablation. The majority were limited to Clavien-Dindo grade I/II events (96%; Table 4). One man developed postcryotherapy prostatic infection with MRI findings that suggested the presence of an abscess; cystoscopy and transurethral unroofing were performed without demonstration of frank pus (Clavien-Dindo grade IIIB). There were no significant differences in rates of any adverse events (29% vs 53%; p = 0.092) or severe adverse events (0% vs 5%; p = 0.3) between the MRI-visible and MRI-invisible groups.

Discussion
PGA is an emerging treatment option for localized PCa with the aim of oncological control and preservation of HRQoL. While previous PGA series have evaluated oncological and functional outcomes for MRI-targetable lesions, our series is the first to compare outcomes between MRI-visible and 12 (12)(13)(14) 12 (12)(13)(14) 13 (   MRI-invisible lesions. In addition, we present biopsy endpoints in accordance with FDA-driven expert consensus for evaluation of PGA as a therapeutic option in light of a significant evidence gap, as defined by AUA and European Association of Urology guidelines [3,21,22]. We found overall recurrence rates of 34% at 12 mo at 43% at 24 mo. While MRI-visible cancers had a higher tumor volume according to the maximum cancer core length on biopsy, consistent with prior work demonstrating that MRI detection sensitivity correlates with tumor size [23], there was no significant difference in recurrence rate for MRI-visible versus MRIinvisible lesions at 12 mo (39% vs 19%) or 24 mo (47% vs 31%). Our results reveal higher recurrence rates after cryoablation in comparison to other series, but different definitions of cancer recurrence have been used. For example, Shah et al [9] found a failure-free survival rate of 90.5% at 3 yr among 122 patients who underwent cryoablation, and the surveillance protocol involved PSA testing, MRI, and ''forcause'' biopsies if recurrence was suspected. Baskin et al [24] observed a failure-free survival rate of 96% at 2 yr after cryoablation, with failure defined as transition to radical treatment for biochemical recurrence according to the Phoenix criteria [24].
There is significant variation in PGA cancer control endpoints across studies. Expert consensus advocates for objective oncological endpoints such as PCa recurrence on biopsy rather than the need for salvage RP or RT [8,22]. Multiple series have defined recurrence as the need for salvage treatment, and few series capture post-PGA surveillance biopsy endpoints [9][10][11][12][13]25,26]. In an analysis of 160 men who underwent hemigland cryoablation, of whom 104 who had follow-up biopsy, Oishi et al [25] found that recurrence-defined as clinically significant PCa on surveillance biopsy-was evident in 15% at 3 yr and 37% at 5 yr. Although our treatment success rate is lower than in this study, the results may reflect differences such as our greater use of PGA rather than a hemigland approach and a greater proportion of subjects (89%) with surveillance biopsy data in our study.
Recent studies evaluating HIFU and MRgFUS used a pathological endpoint based on surveillance biopsy to define oncological efficacy, consistent with FDA-defined outcomes as a pathway towards approval for a PCa indication [12][13][14][15]26,27]. Our study examined the same biopsydefined endpoint through an initial surveillance biopsy 6-12 mo after PGA and, if negative for cancer, a second surveillance biopsy at 24 mo after PGA. Results from a   [14]. This finding is significant because the trial used more stringent patient selection criteria than in our study, as well as real-time in-bore targeting. While expert consensus is to perform PGA on MRIvisible lesions, it is unclear if PGA may be performed for MRI-invisible lesions. Our study is the first to demonstrate that oncological and functional outcomes after PGA are similar for subjects with MRI-visible versus MRI-invisible lesions.
Our results also demonstrate a minimal change in EPIC-CP scores at 12 mo after cryoablation, which compares favorably to patient-reported outcomes after whole-gland therapy with surgery or radiation [4]. These favorable functional outcomes are similar to those in other cryoablation    PGA series [9,24,25]. The rate of adverse events was 35%, and the rate of severe adverse events (Clavien-Dindo grade III) was low at 1%, both of which are comparable to previously reported outcomes [9]. Our study must be interpreted in the context of its design. First, our definition of MRI-invisible lesions included PCa found on systematic biopsy that was on the opposite side or not adjacent to the MRI target(s). While independent review of prostate MRI and pathology reports was performed to define these lesions, discrepancies may be possible if performed by multiple independent reviewers. In addition, the proportion of clinically significant PCa detected on systematic biopsy outside of the MRI region of interest can vary according to which pathological endpoints are used. Our definition of MRI-invisible PCa is based on positivity in a systematic biopsy core(s) rather than MRI correlation with whole-mount specimens, whereby a higher proportion of men have MRI-invisible cancer [16,23,28]. Second, our primary outcome of interest was overall recurrence rather than in-field recurrence of clinically significant PCa. Although we assessed in-field and out-of-field recurrences after PGA, this classification is challenged by inaccuracies in post-treatment MRI. Cryoablation may alter the prostate size and orientation on both the treated ipsilateral and untreated contralateral sides, thereby affecting the reliability of targeted biopsies in the treated regions [29]. In addition, overall recurrence, rather than in-field recurrence, is more clinically relevant and ultimately guides clinical decision making. Third, our study has limited follow-up with a median time of 44 mo. In our survival analysis comparing MRI-visible and MRI-invisible PCa, a significant number of subjects were censored after the first 12 mo, either because of recurrence or lack of a second surveillance biopsy. Although we report salvage treatment plans and metastases, long-term outcomes such as cancer-specific and overall mortality have not matured. Nevertheless, of the 42 men with at least 2 yr of follow-up, 22 (52%) received at least two surveillance biopsies after treatment, which is consistent with consensus recommendations [8,22,30] and less commonly reported than PSA or salvage therapy endpoints for cancer control. Additional limitations include our retrospective study design and the absence of a comparison arm.

Conclusions
PGA is a safe treatment option for clinically localized PCa, with minimal effects on HRQoL and a favorable adverse event profile. Persistence or recurrence of clinically significant PCa was evident in approximately half of patients treated with partial-gland cryoablation. Although our recurrence-free survival rates are somewhat lower than previously published outcomes, our study used pathological endpoints to define cancer recurrence and is the first to demonstrate similar outcomes for MRI-visible and MRIinvisible lesions. While a central dogma for PGA is that appropriate candidates for treatment are men with MRIvisible lesions, we demonstrated that men with systematic biopsy-positive, MRI-invisible lesions may be treated with similar safety, HRQoL, and cancer control outcomes. Larger sample sizes and prospective trials are needed to validate our findings.
Author contributions: Jim C. Hu had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Zhu, Hu.
Analysis and interpretation of data: Zhu, Margolis, Hu.
Drafting of the manuscript: Zhu, Zhang, Hu.