MRI Can Replace Early Protocol Biopsy in Patients Undergoing Focal Cryoablation for Prostate Cancer

Abstract

Introduction and Objectives:

Assessing oncological success following focal ablation for prostate cancer (PCa) includes prostate-specific antigen (PSA) response and imaging. However, the value of protocol biopsy remains uncertain. Consensus recommendations include follow-up multiparametric MRI (mpMRI) and biopsy despite variable imaging quality, interpretation, and biopsy performance. We aim to determine mpMRI performance characteristics postablation for early in-field (within the ablation zone) failure following focal cryoablation (FC).

Methods:

Patients receiving FC from January 1, 2017, to April 21, 2023, at Michigan Medicine were enrolled in a multi-institutional, institutional review board-approved prospective registry. Per protocol, PSA, mpMRI, and ultrasound-MR fusion biopsy of the ablation bed were obtained at 6 to 12 months postablation. Residual PCa was suspected on mpMRI if there was persistent enhancement and impeded diffusion near the ablation zone colocalizing to the intended ablation target. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of postablation mpMRI for Gleason Grade Group (GG) ≥2 PCa were calculated. Chi-squared test was used to perform bivariate analysis.

Results:

A total of 76 patients underwent primary ablation, postablation mpMRI, and protocol biopsy. Eight patients underwent repeat cryoablation with postsalvage cryoablation mpMRI and biopsy (N = 84 postablation events). Postablation mpMRI showed persistent PCa in 13.4% (11/84). Postablation biopsy showed GG ≥2 PCa in 7.1% (6/84) of target lesions. MpMRI sensitivity, specificity, PPV, and NPV for detecting untreated GG ≥2 PCa postablation were 83.3%, 92.3%, 45.5%, and 98.6%, respectively, with significant association between positive MRI and biopsy detection of GG ≥2 PCa (p < 0.0001). The positive and negative likelihood ratios for residual disease detection were 10.8 and 0.18.

Conclusion:

Postablation mpMRI has a high sensitivity, NPV, and specificity for detecting untreated GG ≥2 PCa. If negative, near-term “protocol” biopsy may be safely avoided. Investigation into causes of false positive and negative postablation mpMRI will help identify those who warrant per-protocol biopsy.

Introduction

In 2023, 288,300 men were newly diagnosed with prostate cancer (PCa).^1,2 Of those, 95% will have clinically localized disease without evidence of metastasis.³ Recent data have shown low mortality rates (≤3.1%) for men with localized PCa, regardless of whether managed with long-term active surveillance or radical surgery/radiation.⁴ These data, taken in the context of often unacceptable morbidity of radical treatment (i.e., long-term [7–12 years posttreatment] urine leakage: 3%–24%, potency sufficient for sexual intercourse: 18%–27%, and bowel dysfunction: 6%–12%) compared with 9% to 11%, 30%, and 6% with active surveillance, respectively, have emphasized the value of conservative localized PCa management.⁵ Men who choose not to pursue radical PCa treatment are most commonly offered active surveillance, with frequent monitoring of disease progression via serial prostate-specific antigen (PSA) testing, prostate multiparametric MRI (mpMRI), and prostate biopsies.⁶

Recent advances in prostate imaging and focal treatment modalities, including high-intensity focal ultrasound and cryotherapy, have allowed urologists to better identify and treat localized PCa while sparing nondiseased nerve and prostate tissue. These advancements enable urologists to offer focal therapy as an alternative to radical treatment while sparing men the anxiety of living with untreated cancer with metastatic or lethal potential. As current PCa risk stratification is unable to reliably discriminate between indolent vs aggressive PCa, the role of focal cancer treatment continues to demonstrate promise as a curative treatment with improved urinary and sexual function outcomes.⁷

Although the aim of focal therapy is curative treatment for lethal PCa foci, there is an absence of long-term data regarding oncologic control, and therefore, it is currently considered investigational by the American Urological Assocation.⁸ With limited comparative data, consensus guidelines recommend that patients receive follow-up PSA testing, mpMRI, and biopsy as part of posttreatment oncological surveillance. The most recent recommendations state that an mpMRI with systematic 12-core and targeted biopsy of the ablation zone should be performed at 6 to 12 months postprocedure.⁹ With an absence of data demonstrating the clinical value of a mandated protocol prostate biopsy rather than tissue sampling “for cause,” the average cost of a prostate biopsy being more than $2000 to the patient, patient experience during biopsy, and nonzero risk of infectious complications following both transperineal and transrectal prostate biopsies, we aimed to determine mpMRI performance characteristics postablation for in-field (within the ablation zone) failure following focal cryoablation (FC).^10,11

Methods

Patients receiving FC for localized PCa at Michigan Medicine from 01/01/2017 to 04/21/2023 were enrolled in an institutional review board (IRB)-approved, multi-institutional, prospective registry. Prior to treatment, patients received a prostate mpMRI, scored using Prostate Imaging Reporting and Data System (PI-RADS) v2, and prostate biopsy. We included all patients treated at Michigan Medicine during this time period in our data collection. Patients were excluded in our analysis if they did not receive a postablation biopsy or mpMRI within 6 to 12 months (± 90 days) of their cryoablation.

Patients underwent prostate cryoablation with either the Varian (Palo Alto, California) or Boston Scientific (Marlborough, Massachusetts) cryotherapy platforms. All procedures were performed with software-based MR/US fusion-guidance utilizing a 10 mm treatment margin. Treatment consisted of two freeze-thaw cycles and adequacy of treatment determined by coverage with appropriate isotherms achieving ≤−20°C or via confirmation with thermocouples.

Per protocol, PSA, mpMRI, and ultrasound-MR fusion biopsy of the ablation bed were obtained at 6 months postablation. The prior ablation zone was segmented accounting for changes in prostate volume because of remodeling after treatment. Sampling was performed across the ablation zone at 3 to 5 mm intervals, which include penumbra/margin biopsies. Residual PCa was suspected on mpMRI if there was persistent enhancement and impeded diffusion near the ablation zone colocalizing to the intended ablation target as demonstrated in Figure 1b. Patient demographic, pre and posttreatment PSA, MRI, and biopsy data were collected from the electronic medical record and entered into an online Research Electronic Data Capture database. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of postablation mpMRI for Gleason Grade Group (GG) ≥2 PCa of any size, GG ≥1 PCa ≥4 mm, and any cancer were calculated. Chi-squared tests was used to perform univariable analyses. A univariate and multivariate logistic regression was conducted to examine the association between preoperative variables and infield recurrence within 12 months. The predictors included patient age, patient race, preoperative PSA, preoperative Gleason score within ablation target, preoperative PSA density, preoperative Gleason score within the systematic biopsy specimens, preoperative PI-RADS v2 scoring within the ablation target, preoperative prostate volume, suspicion of residual disease on postoperative mpMRI, and postoperative percent PSA change.

FIG. 1.

(A). Pretreatment PI-RADS 4 observation in the left lateral midgland peripheral zone. Preablation axial T2-weighted imaging (left) and axial diffusion-weighted imaging b-2400 imaging demonstrating hypointensity in the peripheral zone on T2-weighted imaging and impeded diffusion/hyperintensity on diffusion-weighted imaging. (B) 6 months postablation axial T2 weighted-imaging (left), diffusion-weighted imaging b-1600 (middle), and dynamic contrast-enhanced subtraction (right) imaging demonstrating residual hypointensity in the peripheral zone on T2 weighted-imaging and hyperintensity on diffusion-weighted imaging consistent with untreated disease. PI-RADS = Prostate Imaging Reporting and Data System.

Results

A total of 76 patients undergoing 84 cryoablations, postablation mpMRI, and protocol biopsy were included. Patient-level characteristics are presented in Table 1. Eight patients subsequently underwent repeat cryoablation with postsalvage ablation mpMRI and biopsy (N = 84 postablation events). Postablation mpMRI showed possible residual cancer in 13.1% (11/84). Postablation biopsy of the target lesion showed GG ≥2 PCa in 7.1% (6/84) patients. Prostate mpMRI sensitivity, specificity, PPV, and NPV for detecting GG ≥2 PCa postablation were 83.3%, 92.3%, 45.5%, and 98.6%, respectively. The positive and negative likelihood ratios for detecting clinically significant disease were 10.8 and 0.18, respectively. Prostate mpMRI sensitivity, specificity, PPV, and NPV for detecting postablation GG ≥1 cancer ≥4 mm were 66.6%, 93.3%, 54.5%, and 95.9%, respectively. Test characteristics were identical for detecting any cancer.

Table 1.

Study Population Details

Patient characteristics	Study participants (n = 76)
Age, median (IQR)	70 (64.25, 73)
Race, n (%)
Black	7 (9)
White	68 (89)
Asian	1 (1)
Comorbidities, n (%)
Diabetes	12 (16)
Hypertension	40 (53)
Coronary artery disease	9 (12)
Heart failure	1 (1)
Renal insufficiency	3 (4)
PSA (ng/mL), mean (std)	9.66 (7.3)
PSA density (ng/mL/cc), mean (std)	0.23 (0.21)
PI-RADS v2 score
PI-RADS 3, n (%)	3 (4)
PI-RADS 4, n (%)	43 (57)
PI-RADS 5, n (%)	28 (37)
Unscored, n (%)	2 (3)
Gleason Grade Group, n (%)
Grade Group 1	5 (7)
Grade Group 2	54 (71)
Grade Group 3	14 (18)
Grade Group 4	2 (3)
Unscored	1 (1)

IQR = interquartile range; PI-RADS = Prostate Imaging Reporting and Data System; PSA = prostate-specific antigen.

Univariate analysis showed that preoperative PSA density (p < 0.005) and suspicion of residual disease on postablation mpMRI (p < 0.0001) were significantly associated with biopsy detection of GG ≥2 PCa within the ablated field. Multivariate analysis of demographic and oncologic characteristics associated with in-field recurrence is presented in Table 2. Although preoperative PSA density demonstrated a statistically significant association with risk of persistent disease on univariate analysis, it was not significant on multivariate analysis (p = 0.053). However, suspicion of residual disease on postop mpMRI remained significantly associated with an increased risk of persistent disease on multivariate analysis (p < 0.001; pseudo-R ² 0.3861).

Table 2.

Multivariate Analysis of Demographic and Oncologic Characteristics Associated with In-Field Recurrence at mpMRI

Independent variables	Coefficient	p > z	95% confidence interval
Postop MRI suspicion of residual disease	0.499	<0.001	0.312 to 0.686
Postop % PSA change	−0.143	0.115	−0.321 to 0.036
Preop MRI PI-RADS score of the primary lesion	0.020	0.636	−0.065 to 0.106
Preop PSA density	0.297	0.053	−0.005 to 0.599
Constant	−0.011	0.956	−0.395 to 0.374
R ²	0.3861

mpMRI = multiparametric MRI.

Discussion

Our data suggest that postablation mpMRI has a high NPV, specificity, and positive likelihood ratio for detecting residual GG ≥2 PCa. The most recent consensus guidelines for PCa surveillance following focal therapy were published in 2020 and recommended obtaining a systematic 12-core and 4-core targeted biopsy of the ablated region at 12 months. However, those were not evidence-based recommendations. Our data demonstrating a sensitivity of 83.3%, NPV of 98.6%, specificity of 92.3%, positive likelihood ratio of 10.8, and negative likelihood ratio of 0.18 for mpMRI at 6 months may warrant deferral of near-term “protocol” prostate biopsy with a negative postablation mpMRI. Our secondary analysis showing a significant association between suspicion of residual disease on postablation mpMRI and in-field recurrence on univariate and multivariate analysis further supports the usage of mpMRI in assessing treatment changes. Importantly, our finding that preoperative PSA density is associated with a significant association with in-field recurrence on univariate analysis is in line with prior evidence showing an increased risk of biochemical recurrence, positive surgical margins, and adverse pathological findings following radical prostatectomy in patients with higher preoperative PSA density.^12

–17 This prior evidence suggesting an association between higher PSA density and more aggressive tumor biology may explain the increased risk of in-field recurrence following FC found in our study.¹⁸ Additionally, elevated PSA density reflects a greater volume of cancer related to prostate size. This factor may increase the risk of in-field failure in the immediate term and support the usage of hemiablation or larger treatment margins in patients with a high PSA density (>0.15) preoperatively. PSA density was not significant on multivariate analysis, and we believe this is likely because of sample size limitations (i.e., possible viable untreated disease identified in only 11 of 84 ablations).

Although prior research has shown that preoperative PSA, PI-RADS v2 score, and Gleason grade are associated with biochemical recurrence following radical prostatectomy, the absence of association between these variables and in-field recurrence at 12 months in our analysis may be because of the time period at which we assessed for recurrence.^{16,17,19

–23} These variables are time-dependent variables associated with increased risk of recurrence with continued longitudinal follow-up. In contrast, tumor-associated factors at the time of treatment, including preoperative PSA density, lesion size, and treatment type, may be most associated with early, localized recurrence as assessed in our study. Specifically, treatment associated factors leading to inadequate treatment and thus early in-field recurrence include the use of fused preoperative mpMRI and transrectal ultrasonography (rather than of in-mpMRI bore treatment), which introduces the possibility of registration error between the preablation mpMRI and intraoperative transrectal ultrasonography, thermal sink, and urethral warming. As such, a follow-up analysis of recurrence at 36 and 60 months posttreatment is warranted.

This study was limited in that there was a low in-field recurrence rate of 11.8%, contributing to the high observed NPV. Notably, this study’s low in-field recurrence rate is concordant with recently published data showing in-field recurrence rates of 3% to 16.7%.^16,24,25 However, despite this limitation, mpMRI had a 83.3% sensitivity and 0.18 negative likelihood ratio for detecting clinically significant disease and a 66.7% sensitivity for detecting any cancer. The only previously published data on mpMRI performance following FC demonstrated a sensitivity of 20% for the detection of any cancer.¹⁶ This discordance in data may be because of the previous study’s smaller sample size, interinstitutional reliability differences in mpMRI evaluation, and biopsy performance. Therefore, it is essential to involve an experienced radiologist familiar with prostate imaging in the context of PCa focal therapy in assessing postablation treatment changes. Moreover, we emphasize that all pre and postablation mpMRI images should be made available to urologists and radiologists during treatment and follow-up to allow for adequate comparison of treatment effects. Figures 1a and 1b demonstrate the value of mpMRI, as MRI findings commonly associated with PCa, such as impeded diffusion on diffusion-weighted imaging, may reflect physiological posttreatment changes instead of residual PCa. As such, we recommend that urologists and radiologists compare T2-weighted, diffusion-weighted, and dynamic contrast-enhanced subtraction phases of the postablation MRI to make the best assessment of treatment success. Coagulative necrosis can mimic cancer on diffusion-weighted and T2-weighted images; therefore, enhancement is necessary to confirm the finding is solid before considering it viable tissue. Colocalization to the pretreatment tumor volume can help avoid errors.

Our multivariate analysis further demonstrates the utility of postablation mpMRI in assessing in-field treatment failure. This study’s relatively low pseudo-R ² value of 0.3861 demonstrates that predictors of in-field recurrence, including patient age, race, preoperative PSA, preoperative PI-RADS v2 score, preoperative PSA density, preoperative Gleason score, and postablation percent change in PSA, account for a low to moderate amount of the variance in in-field recurrence outcomes. In contrast, mpMRI has a high sensitivity, high specificity, and a high NPV for the detection of clinically significant PCa on prostate biopsy. Furthermore, suspicion of residual disease at MRI was the only variable significantly associated with in-field recurrence in our multivariate analysis. Although the percent change in PSA was not significantly associated with recurrence, 33% (1/3) of patients with a rising PSA following treatment were positive for clinically significant PCa in the ablated region, demonstrating the importance of postablation PSA monitoring. As such, we believe that patients may be more carefully selected for individualized biopsy after considering factors such as preablation PSA density, PI-RADS v2 primary score, postablation imaging findings, and postablation PSA monitoring. A limitation of our study is that our study solely included patients treated with FC, and therefore, our data may not be directly extrapolated to other ablative treatments. However, future investigation into alternative treatment modalities, causes of false positive and false negative postablation mpMRI, and mpMRI evaluation using the newly created Prostate Imaging after Focal Ablation and the Transatlantic Recommendations for Prostate Gland Evaluation After Focal Therapy scoring systems will further assist urologists in identifying those who warrant per-protocol biopsy.^26,27

Footnotes

Ethics Approval

This study was conducted under the IRB: HUM00212649. The IRB approving institution was Michigan Medicine.

Authors’ Contributions

P.B., E.O., K.D., M.J., M.A., and A.K.G.: Collection of data and analysis; E.O., K.D., M.J., M.A., M.S.D., J.S.M., and A.K.G.: Manuscript editing; M.S.D.: MRI verification; J.S.M. and A.K.G.: Clinical care; P.B. and A.K.G.: Writing.

Author Disclosure Statement

A.K.G. has the following disclosures: Sonablate Corporation—Consultant; HIFU Prostate Services—Consultant; Francis Medical—Research; Angiodynamics—Research; Nanospectra Biosciences—Research; Other disclosure not relevant: CIVCO—Consultant; Lina Medical—Consultant; Boston Scientific—Consultant; Levee Medical—Consultant; Veracyte—Speaker/Consultant; BK Medical—Consultant. Other authors have nothing to disclose.

Funding Information

There are no funders to report for this submission.

Abbreviations Used

References

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USCS Data Visualizations. Available from: https://gis.cdc.gov/grasp/USCS/DataViz.html [Last accessed: January 13, 2024 ].

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