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Focal therapy
Changing the landscape of prostate cancer treatments
Scheltema, M.J.V.
Publication date
2018
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Citation for published version (APA):
Scheltema, M. J. V. (2018). Focal therapy: Changing the landscape of prostate cancer
treatments.
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PRELIMINARY DIAGNOSTIC ACCURACY
OF MULTIPARAMETRIC MAGNETIC
RESONANCE IMAGING TO DETECT
RESIDUAL PROSTATE CANCER
FOLLOWING FOCAL THERAPY WITH
IRREVERSIBLE ELECTROPORATION
Scheltema MJ, Chang JI, van den Bos W, Böhm M, Delprado W, Gielchinsky
I, de Reijke TM, de la Rosette JJ, Siriwardana AR, Shnier R, Stricker PD
ABSTRACT
Background: It is recommended to perform multiparametric magnetic resonance
imaging (mpMRI) in the follow-up following focal therapy of prostate cancer (PCa).
Objective: To determine the diagnostic accuracy of mpMRI to detect residual PCa
following focal therapy with irreversible electroporation.
Design, setting and participants: Seventy-six patients with biopsy-proven localized
PCa consented for primary irreversible electroporation between February 2013 and March 2016. Final analysis was performed on 50 patients that received follow-up mpMRI at 6 mo, serial prostate-specific antigen (PSA) testing, and transperineal template-mapping biop- sies at 12 mo.
Outcome measurements and statistical analysis: Outfield regions of interest (ROI)
were reported using PI-RADS v2. A binary outcome (suspicious vs. non-suspicious) was given for the infield ablation zone. Sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated for different definitions of significant PCa: (1): Gleason ≥4+3 or Gleason ≥3+3 with a maximum cancer core length ≥6 mm, (2) Gleason ≥3+4 or Gleason ≥3+3 with a maximum cancer core length ≥4 mm, for outfield and infield ROI. Multivariate linear regression analyses evaluated the additional value of nadir PSA.
Results and limitations: Sensitivity, specificity, PPV and NPV of infield ROI was 43%,
86%, 33%, 90% for definition 1 and 38%, 86%, 33%, 88% for definition 2, respectively. For outfield ROI this was 33%, 82%, 20%, 90% for definition 1 and 38%, 86%, 50%, 80% for definition 2. PSA had no additional value in predicting residual significant PCa. Limitations include retrospective design, single reader and low incidence of residual PCa.
Conclusions: Our preliminary data suggest that mpMRI can rule out high-volume
residual PCa. However, follow-up biopsies should still be performed to determine oncological control.
Patient summary: MpMRI is able to detect high-volume significant PCa following focal
therapy. Prostate biopsies are still required in the follow-up of focal therapy as (low-volume) significant PCa is being missed by mpMRI.
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INTRODUCTION
Focal therapy is gaining traction as prostate cancer (PCa) treatment for carefully selected patients with localized disease.1 A variety of focal ablative modalities are
available, including irreversible electroporation (IRE).1 IRE ablates tumorous tissue by
applying a direct current between two or more needle electrode pairs.2 When the cell
membrane is exposed to multiple consecutive electrical pulses, membrane instability and permeability is induced causing subsequent cell death.3 Initial phase 1-2 trials have
demonstrated the safety and feasibility of IRE for focal therapy in localized PCa.4–8
Adequate PCa localization is the cornerstone for lesion-based ablative therapy. Multiparametric Magnetic Resonance Imaging (mpMRI) of the prostate is the leading imaging modality to provide clinicians with information on lesion location and geometry. Consensus guidelines on the use of mpMRI with focal therapy recommend to perform mpMRI both for treatment planning and follow-up.9 The diagnostic accuracy
of mpMRI of PCa localization and diagnosis has been extensively evaluated in the past years. Among the studies10 evaluating the PCa diagnostic value of mpMRI, the recently
published PROMIS trial11 showed a superior PCa detection rate of mpMRI over standard
transrectal prostate biopsies in biopsy-naive patients, validated by use of transperineal template mapping biopsies (TTMB). The growing evidence for mpMRI in PCa care resulted in the application of mpMRI throughout focal therapy protocols. The follow-up of some trials even deferred standardized follow-up prostate biopsies, relying entirely on the diagnostic accuracy of mpMRI to detect residual PCa.12 However, except for the
study by Dickinson et al13, no diagnostic accuracy studies have been published on mpMRI
in the follow-up of focal therapy. These authors evaluated the diagnostic accuracy of prostate-specific antigen (PSA) and mpMRI for detection of infield (i.e. prostate region previously ablated) residual PCa only, using targeted biopsy data (median 6 cores) from 3 different trials.13
In order to advance the field of focal therapy, validation of the follow-up mpMRI needs to be achieved including both infield and outfield (i.e. prostate tissue previously not ablated). Therefore we aimed to determine the diagnostic accuracy of mpMRI to detect residual PCa following focal therapy with IRE.
MATRIALS AND METHODS
Ethical approval
Institutional review board approval was obtained from the Human Research Ethics Committee to acquire and analyse oncologic data (HREC approval SVH 16/110). Written informed consent was obtained from all patients to perform focal IRE treatment and follow-up studies.
Study design and participants
Retrospective analysis of prospectively acquired data was performed on patients that underwent IRE for biopsy-proven, treatment-naïve localized PCa between February 2013 and March 2016. Preoperative diagnosis and disease localization were performed using PSA, mpMRI (in all patients), and transrectal biopsies or TTMB. Treatment planning was based on biopsy and mpMRI results. Following IRE, patients underwent serial PSA testing, mpMRI (6 mo) and TTMB (~12 mo) as part of our institutional protocol following the consensus guidelines on trial design.14 Patients that received both follow-up mpMRI
and TTMB were included for final retrospective interpretation of prospectively acquired data (Figure 1) following the Standards for Reporting Diagnostic accuracy studies (STARD15).
Study procedures Irreversible Electroporation
All patients were positioned in the lithotomy position under general anesthesia and deep-muscle paralysis. An indwelling catheter was placed to drain the bladder. Biplanar transrectal ultrasound (TRUS) (BK Medical, Herlev, Denmark) and a template grid were used to place 4-6 electrode needles via the perineum to surround the PCa lesion. A 5-10mm safety margin was applied surrounding the targeted lesion, which was based on biopsy and pretreatment mpMRI. The active tip length varied between 1 to 2 cm. The interelectrode distance was measured using TRUS and entered into the Nanoknife system® (AngioDynamics, New York, USA). Ten pulses were delivered to test the obtained
direct current. The remaining 80 treatment pulses were delivered if the achieved current levels were appropriate (20-40 Ampere). Patients underwent a trial of void either at 2 or 5 days following IRE, depending on pre-existing lower urinary tract symptoms.
Multiparametric MRI
The index test used for this study was mpMRI, which was executed following the recommendations of the Prostate Imaging and Reporting and Data System (PI-RADS) steering committee (first and second version).16 The majority of patients had their
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follow-up mpMRI (43/50, 86%) done in a single center of expertise. Central review was done by an experienced radiologist for the remaining scans that were performed elsewhere (7/50, 14%). The radiologist was blinded to histopathology, had access to pretreatment biopsy, mpMRI and PSA data, and has reported more than 5000 mpMRIs (RS). All scans were performed on a 3.0 Tesla magnet, including T2-weighted, dynamic contrast enhanced (DCE) and diffusion weighted imaging (b-value 0, 800 s/mm2 and
1500 s/mm2) (DWI), with the use of a cardiac coil. All mpMRIs were reported according
to PI-RADS v216, using the standardized 5-point PI-RADS by lesion location to report
the likelihood of significant PCa in untreated prostate tissue (i.e. outfield). PI-RADS 3-5 was classified as significant disease and evaluated separately. Both treated prostate tissue (i.e. infield) and adjacent regions of interest (ROI) were reported as part of the ‘infield region’, as the original ablation zone is often not clearly defined at 6 mo due to prostate deformation and local inflammation/fibrosis. A binary result for significant disease (suspicious vs. non-suspicious) was given for treated prostate regions (i.e. infield). Suspicion for residual disease was based on a focal abnormality with restricted water diffusion on DWI and hyperperfusion on DCE. Identified ROIs were indicated on the transperineal template used for TTMB (Supplementary Figure 1).
Transperineal template mapping biopsies
TTMB are considered to be the gold standard for PCa diagnostics or follow-up and therefore used as reference test. TTMB were performed under general anaesthesia and antibiotic prophylaxis. A template was used to subdivide the prostate into multiple regions (Supplementary Figure 1). Four targeted cores were taken from lesions <15mm in diameter on MRI, whereas 1 targeted core was taken from lesions >15mm in diameter as these lesions often included multiple template locations and cores. Biopsies were guided by a template grid, biplanar TRUS (BK medical, Herlev, Denmark) and mpMRI-fusion (BioJet, DK Technologies, Germany). The use of mpMRI-mpMRI-fusion depended on lesion size and visibility on ultrasound. Lesions with a diameter <10 mm, outside the template or not visible on TRUS were targeted using system fusion, whereas hypoechoic lesions with a diameter of >10 mm were targeted with cognitive mpMRI-fusion. Three different urologists performed follow-up biopsies that each have >8 years experience with TTMB. Biopsy histopathology was centrally reported by a specialized uro-pathologist in accordance to the International Society of Urological Pathology protocol.17 The
definitions by Ahmed et al.18 were used for significant disease on TTMB: Definition 1)
Gleason ≥4+3 or Gleason ≥3+3 with a maximum cancer core length (MCCL) of ≥6 mm and Definition 2) Gleason ≥3+4 or Gleason ≥3+3 with a MCCL of ≥4 mm. The rationale for these definitions was to obtain sensitivity of ≥95% to predict lesions of ≥0.5 mL and ≥0.2 mL for definition 1 and 2, respectively. These definitions adhere to the most recent
focal therapy consensus guidelines defining the ideal case as localized, discrete Gleason ≥3+4.19 The common terminology criteria for adverse events (CTCAE) v4 were used to
register TTMB adverse events by chart review. Prostate Specific Antigen
Serial PSA testing was performed at baseline, 3 mo, 6 mo, 9 mo, and 12 mo. The lowest postoperative PSA was classified as nadir PSA. The nadir PSA was evaluated as absolute value and PSA density using the prostate volume on follow-up mpMRI.
Statistical Analysis
For comparison of the index (mpMRI) and reference (TTMB) test a 2x2 contingency table was used to calculate the sensitivity, specificity, PPV and NPV of ROI on mpMRI with 95% confidence intervals (CI) for both definitions of significant disease. This was calculated for infield (suspicious), outfield (PI-RADS 3-5) and whole-gland ROI separately. Multivariate linear regression analyses were performed to evaluate the additional value of nadir PSA (absolute value and density) to detect residual infield/outfield PCa (definitions 1 and 2). Statistical tests were performed using SPSS v23 (SPSS Inc., Chicago, IL, USA) and p <0.05 was considered statistically significant.
RESULTS
Seventy-six patients were treated with primary IRE for localized PCa. Fifty patients underwent both follow-up mpMRI and TTMB and were included for final analysis. Figure 1 illustrates the inclusion flowchart. The baseline characteristics are displayed in Table 1. Imaging results of patients with follow-up mpMRI that were excluded are summarized in supplementary Table 1. Seven patients had 2 lesions on their baseline mpMRI. Of these patients two harbored multi-focal PCa that was treated with two ablations. Overall oncological outcomes following IRE
Biopsy outcomes
TTMB were performed on all 50 patients, with a median number of cores taken of 28 (IQR 24 – 31). No high-grade adverse events occurred following TTMB (≥grade 2 on CTCAE v4). Thirty-two patients had no significant PCa (neither definition 1 or 2) and 13 had residual definition 1 significant PCa on TTMB. Using definition 2 significant PCa 18 patients had residual disease. One patient had two lesions with definition 1 cancer, whereas five patients had two lesions with definition 2 cancer.
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Table 1. Patient characteristics
(median, IQR) Variable Value Age (years) 67 (63 – 71) PSA (μg/L) 6.1 (3.3 – 8.3) Clinical stage T1c 3 (6%) T2a 31 (62%) T2b 8 (16%) T2c 8 (16%) Baseline biopsy TTMB 34 (68%) TRUS 12 (24%) Targeted only 4 (8%) Number of cores taken 24 (14 – 33) Number of positive cores 4 (2 – 6)
Gleason Score 6 (high-volume) 6 (12%) 3+4 32 (64%) 4+3 11 (22%) ≥4+4 1 (2%) Baseline mpMRI 1.5 Tesla 5 (10%) 3.0 Tesla 45 (90%) Prostate volume (mL) 39 (30 – 57) Lesion diameter (mm) 9 (6 – 15) ADC value (mm2/s) 855 (620 – 1000) T2 visible 47 (94%) >1 lesion on MRI 7 (14%) PI-RADS 2 3 (6%) 3 Peripheral zone 3 Anterior/Transition zone 8 (16%) 0 4 Peripheral zone 4 Anterior/Transition zone 15 (30%) 7 (14%) 5 Peripheral zone 5 Anterior/Transition zone 11 (22%) 6 (12%)
* In case of >1 lesion the highest PI-RADS was displayed. Abbreviations: IQR, interquartile range; PSA, prostate specific antigen
Table 2. Oncological and imaging results
(median, IQR)
Variable Value
Nadir PSA (μg/L) 1.9 (1.1 – 4.7) PSA density (μg/L per cc) 0.0572
(0.0354 – 0.0913)
Follow-up biopsy lesions
No or insig. PCa 32 GS 3+3, ≥4mm* GS 3+3, ≥6mmx 7 4 GS 3+4, any* GS 3+4, ≥6mmx 8 2 GS 4+3, any# 5 GS ≥4+4, any# 3
mpMRI results n= (% true positivex)
No ROI 33 Infield ROI 9 (33%) Outfield PI-RADS 3 Peripheral zone Anterior/Transition zone 8 5 (20%) 3 (33%) Outfield PI-RADS 4 Peripheral zone 1 (0%) 1 Outfield PI-RADS 5 0
Lesions missed by mpMRI
GS 3+3, ≥4mm* GS 3+3, ≥6mmx 4 2 GS 3+4, any* GS 3+4, ≥6mmx 4 1 GS 4+3, any# 4 GS ≥4+4, any# 3
*: definition 2 including definition 1, x: definition 1 only, #:
Definition 1 and 2. Abbreviations: IQR, interquartile range; PSA, prostate specific antigen; GS, Gleason Score; ROI, region of interest
Figure 1. Inclusion flowchart of patients included for final analysis
PSA outcomes
Absolute median nadir PSA was 1.9 μg/L (IQR 1.1 – 4.7) and median PSA density was 0.0572 μg/L per cc prostate (IQR 0.0354 – 0.0913). The absolute PSA nadir had no additional value to predict infield and outfield definition 1 (p=0.12 and p=0.60) or definition 2 (p=0.18 and p=0.083) residual significant PCa. Likewise, nadir PSA density showed no additional value to predict infield and outfield definition 1 (p=0.093 and p=0.68) or definition 2 (p=0.14 and p=0.16) residual significant PCa. Table 2 summarizes the oncological and mpMRI results.
Diagnostic accuracy of mpMRI to detect residual PCa
A total of 18 ROI on mpMRI were identified in 17 patients (34% positive MRI, n=17/50). Table 2 shows the ROI classification and locations. Of the seven patients that had two separate lesions on their baseline MRI, 3 patients had persisting lesions on follow-up MRI and 2 patients harbored significant disease in that region.
The sensitivity, specificity, PPV and NPV to detect residual definitions 1 and 2 significant PCa are displayed in Table 3 showing the infield, outfield and whole-gland separately, including the numerators/denominators and 95% CIs. The anatomical concordance of ROI on mpMRI and definition 1 PCa is visualized in Supplementary Figure 2. Figures 2-3 and supplementary figure 3 illustrate various follow-up mpMRI images.
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Table 3. Diagnostic accuracy per definition (fraction, 95% CI)
PCa definition Sensitivity (%) Specificity (%) PPV (%) NPV (%) GS ≥ 4+3 or ≥ 6mm Infield Outfield Whole-gland 43 (,10-82) 33 (,4-78) 38 (,14-68) 86 (,72-95) 82 (,68-92) 70 (,53-84) 33 () 20 ( 31 () 90 () 90 () 76 () GS ≥ 3+4 or ≥ 4mm Infield Outfield Whole-gland 38 (,9-76) 38 (,14-68) 44 (,22-69) 86 (,71-95) 86 (,71-95) 72 (,53-86) 33 () 50 () 47 () 88 () 80 () 70 ()
Abbreviations: CI, confidence intervals; GS, Gleason Score
Legend: The diagnostic accuracy to detect residual prostate cancer is displayed per definition of significant prostate cancer for the infield, outfield and whole-gland. Sensitivity and specificity values are accompanied by 95% confidence intervals. The fractions are the actual numbers from which the diagnostic accuracy is calculated.
Figure 2. Regions of interest on follow-up mpMRI
A-B: True positive example of an in-field lesion on follow-up mpMRI with focal hyperperfusion on DCE (A) and restricted water diffusion on DWI (B) MRI. Follow-up biopsy confirmed this lesion as low-volume Gleason 4+3=7. C-D: False positive in-field lesion with asymmetrical focal hyperperfusion on DCE (C) with focal restricted water diffusion on DWI (D).
Figure 3. Scarring of the ablation zone on follow-up mpMRI.
A-B: Focal region with restricted water diffusion on DWI (A). This region is not suspicious for residual prostate cancer due to the combination of decreased perfusion on DCE (B) and diffuse scarring on T2-MRI (C), and is typical for post-ablative scarring of the ablation zone.
Undetected Prostate Cancer
Thirty-three patients had no ROI on mpMRI. In 10 patients with a negative mpMRI, 9 regions (5 infield/4 outfield) with definition 1 and 12 regions (5 infield/7 outfield) with definition 2 significant PCa were detected on TTMB. Anatomical discordance was present in three patients with a positive mpMRI, one harboring definition 1 significant PCa in a distinct region and two patients with definition 2 significant PCa (all infield). Of all 15 significant PCa lesions that were (discordantly) missed (definition 2), only 3 lesions in 2 patients had a Gleason Score ≥3+4=7 that contained a MCCL of ≥4mm (Table 2). When the definition of significant PCa was adapted to Gleason Score ≥3+4=7 with a MCCL of ≥4mm, the specificity and NPV would improve to 87% and 98% for the infield and 83% and 98% for the outfield, respectively.
DISCUSSION
To our knowledge this report is the first to evaluate the diagnostic accuracy of 3-Tesla mpMRI to detect residual significant PCa following focal therapy for both the infield and outfield regions. These preliminary results suggest that mpMRI is able to detect high-volume residual significant PCa. Despite the high specificity and NPV, significant PCa was still missed (mainly low-volume or high-volume Gleason 6). This may be explained by findings of Villers et al.20 showing that the diagnostic accuracy of mpMRI is dependent
on lesion volume. The PPV and NPV were 86% and 85% for lesions >0.2 mL and 77% and 95% for lesions >0.5 mL, respectively. Care must be taken with the interpretation of the high NPV and specificity, as this may be the result of the low incidence of residual PCa lesions and ROI on follow-up mpMRI.
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ROI on mpMRI require histological confirmation to exclude false-positives since the sensitivity and PPV were poor. This is in line with the low PPV (14 – 44%) of targeted biopsies of ROI on mpMRI after focal therapy and may be explained by local inflammation or fibrosis 13. Consensus guidelines stated that DCE is considered to be the most sensitive
sequence to detect residual PCa.21 Kim et al.22 showed that T2-MRI with DCE was more
sensitive to detect recurrent PCa after whole-gland high-intensity focused ultrasound compared to T2-MRI with DWI. Furthermore, the low incidence of grade and high-volume lesions after IRE negatively impacts the sensitivity. Most new ROI on follow-up mpMRI were low-grade (PI-RADS 3) and it must be emphasized that PI-RADS v216 has
not yet been evaluated post-treatment. Our outfield analysis is limited by the absence of outcome stratification by lesion location due to the limited number of outfield ROI on follow-up mpMRI.
Only the short-term diagnostic accuracy of mpMRI at 6 months was evaluated. Furthermore, the 6-month delay between mpMRI and TTMB may have had a negative impact on the imaging results. Series with a longer follow-up and multiple (immediate) biopsy-endpoints need to provide the long-term diagnostic accuracy.
Our study is limited by the retrospective analysis, heterogeneity of baseline biopsy approach and limited cohort size. TTMB were used as reference test and although this may miss potential residual PCa, it may not be ethically justifiable to perform a radical prostatectomy for whole-gland evaluation. Moreover, the definitions of significant PCa are not validated for our TTMB template. The single reader nature of this study comprises the translatability of our results, however the PI-RADS system has been shown to aid reproducibility.23 The rationale of this approach was that there is very limited experience
with the interpretation of mpMRI following IRE.
At this stage none of the nadir PSA definitions had additional value to predict the presence of residual significant PCa. Time points of serial PSA testing varied, causing heterogenic results. We aimed to obviate this heterogeneity by using the nadir PSA only. Standardized serial PSA testing may provide additional value in predicting residual significant PCa. Though previous findings, focusing on infield ROI only, suggest that nadir PSA is less accurate than mpMRI in predicting residual disease, with an area under the curve of 0.63-0.71 compared to 0.77-0.85, respectively.13
CONCLUSION
Our preliminary data suggest that follow-up mpMRI was able to accurately rule out high-volume residual significant PCa in both the infield and outfield. However, we advise not to defer follow-up biopsies to determine oncological control based on this data due to the preliminary nature, limited incidence of residual disease, poor sensitivity and since low-volume significant PCa is being missed. Further validation is required to confirm our findings.
Acknowledgements
Quoc Nguyen and Anne-Maree Haynes from the Australian Prostate Cancer Research Centre-NSW (APCRC-NSW). CANSTO Database at Garvan Institute. The Australian Commonwealth Department of Health and the St Vincent's Prostate Cancer Centre for financial support. Jayne Matthews for clinical support.
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Supplementary figure 1. Template for transperineal biopsies and mpMRI region(s) of interest
Supplementary figure 2. Anatomical concordance of regions of interest on mpMRI with
Supplementary Table 1. Imaging and biopsy results of patients with follow-up mpMRI that
were excluded for final analysis.
Variable Value (median, IQR)
Patients (n=) 18
Nadir PSA (μg/L) 1.9 (1.1 – 4.7) PSA density (μg/L per cc) 0.0572
(0.0354 – 0.0913) mpMRI results No ROI 15 Infield ROI 1 Outfield PI-RADS 3 Peripheral zone Transition zone 2 2 0 Follow-up biopsy lesions
Not performed 13
No or insig. PCa 4
GS 3+4 1
Abbreviations: IQR, interquartile range; PSA, prostate specific antigen; GS, Gleason Score; ROI, region of interest
Supplementary figure 3. Lesion missed on follow-up mpMRI
A-B: DCE (A) and DWI (B) sequences without any suspicious lesion, however, folup biopsies demonstrated residual low-volume Gleason 4+3=7. Whole-mount pathological examination following robot-assisted prostatectomy confirmed this residual lesion (Gleason 3+4=7, lesion volume of 0.19 mL)
