Abstract
Introduction and Objectives
Patients with persistently elevated prostate specific antigen (PSA) and prior negative 12-core TRUS prostate biopsy (or biopsies) (SBx) are a diagnostic challenge. Repeat SBx or saturation biopsy in this cohort has been shown to have an even lower yield. The aim of our study is to compare the prostate cancer yield of MRI fusion biopsy (FBx) to SBx in a multi-institutional cohort comprised of patients with prior negative biopsies.
Methods
A multi-institutional review was performed on patients with a history of one or more prior negative SBx who underwent multiparametric MRI (MpMRI), followed by FBx and SBx in the same session. Imaging protocol was standardized across institutions and institutional genitourinary radiologists and pathologists reviewed mpMRI and pathology, respectively. Gleason Score (GS) distribution and risk classifications were recorded. Prostate cancer with GS ≥ 3+4 was defined as clinically significant (CS). Univariate and multivariable logistic regression was done to identify predictors of cancer detection on SBx and FBx.
Results
Seven-hundred seventy-nine patients from four institutions were included in the study. Median age and PSA (IQR) were 63.1 (58.5-68.0) years and 8.5 (5.9-13.1) ng/dL, respectively. Median number of prior negative biopsies (range) was 2.0 (1-16). The cancer detection rate (CDR) in the cohort was 346/779 patients (44.4%). Total CS CDR was 30.7% (239/779 patients), with FBx detecting 26.3% (205/779) of patients with CS disease and SBx diagnosing an additional 4.4% (34/779) of patients (p<0.001). Furthermore, of all cancers detected by each modality, FBx detected a higher proportion of CS cancer compared to SBx (One negative biopsy: 75 versus 50%, p<0.001, 2-3 negative biopsy: 76 versus 61%, p =0.006, 4 or more negative biopsies: 84 versus 52%, p=0.006). As such, SBx added a relatively small diagnostic value to FBx for detecting CS disease (One negative biopsy 3.5%, 2-3 negative biopsies 5%, 4 or more negative biopsies: 1%). FBx also outperformed SBx for upgrading patients to an intermediate or high-risk cancer category (GS >6) (One negative biopsy 11.5% versus 3.6%, 2-3 negative biopsy 10.3% versus 5.3%, 4 or more negative biopsies 19.1% versus 1.1%). On multivariable analysis, the number of prior negative biopsies was a significant negative predictor of CS CDR on SBx (p=0.006), but not on FBx (p=0.151).
Conclusions
Using a large multi-institutional cohort, we were able to demonstrate that FBx outperformed SBx in patients with prior negative systematic biopsy. This was due, in part, to the decreasing CS CDR by SBx with increased number of prior biopsies. The yield of FBx stayed constant and did not decrease with increased number of prior negative biopsies. Therefore, repeat SBx alone in patients with multiple prior negative biopsies will be hindered by lower yield and FBx should be utilized concurrently in these patients.
Introduction
In men with suspicion of prostate cancer including elevated prostate specific antigen (PSA) and/or abnormal digital rectal exam (DRE), systematic 12-core transrectal ultrasound-guided biopsy (SBx) has traditionally been a principal method of diagnosing prostate cancer. However, SBx suffers from overdiagnosis of clinically insignificant cancer, underdiagnosis of clinically significant cancer, and has a high false negative rate as ultrasound alone lacks sufficient discriminative ability1–3. Patients with continued suspicion of prostate cancer and negative SBx are a diagnostic challenge and around 38% will undergo repeat SBx over 5 years in an effort to obtain a diagnosis4. Unfortunately, repeating SBx has little efficacy in identifying cancerous lesions, with only 10-25% cancer detection rate even after the fourth repeat SBx5. Moreover, the diagnostic yield of clinically significant (CS) disease relative to insignificant cancer is low and continues to decline with each subsequent biopsy session6. As such, these multiple re-biopsies lead to increased cost, delay in diagnosis and added patient morbidity.
Multiparametric magnetic resonance imaging (MpMRI) fusion biopsy (FBx) has emerged as a promising alternative and addition to SBx in the detection of CS cancer due to its higher propensity to detect CS disease, while decreasing the detection of insignificant disease, relative to SBx7–10. Several single-institution studies have previously demonstrated the benefit of FBx in detecting prostate cancer in patients with prior negative biopsies1,11. However, the analysis of FBx cancer detection as a function of the number of prior negative SBxs was limited in previous studies.
The aim of our study was twofold. First, we sought to investigate the efficacy of FBx relative to SBx in the detection of clinically significant prostate cancer using a multi-institutional cohort comprised of patients with prior negative biopsies. Secondly, within this cohort, we wanted to ascertain the independent effect that number of prior negative biopsies had on FBx and SBx cancer detection, respectively.
Methods
Study population
A retrospective review of prospectively maintained databases of patients who underwent initial mpMRI followed by MRI-TRUS fusion-guided biopsy and systematic 12-core biopsy for prostate cancer suspicion at participating institutions was performed. Patients were enrolled at the following four institutions: National Cancer Institute, Bethesda, MD, Northwell Health, New Hyde Park, NY, University of Alabama at Birmingham School of Medicine, Birmingham, AL and SUNY Upstate Medical University, Syracuse, NY. Patients without a diagnosis of cancer, who had a suspicious prostate lesion on imaging and had a history of one or more prior negative SBx were included in this study. If patients received multiple mpMRI studies and/or fusion biopsies during this time period, only the first session was included for analysis. Institutional review board approval was obtained at each institution.
Image Acquisition and interpretation
MpMRI consisted of triplanar T2 weighted, diffusion weighted imaging and dynamic contrast imaging. All studies met the minimum criteria as outlined by the Prostate Imaging - Reporting and Data System: 2015, Version 2 (PIRADSv2)12. Each institution’s respective uroradiologists reviewed the imaging.
Biopsy Protocol
Patients who had suspicious areas identified on MpMRI underwent both SBx and FBx in the same session utilizing an office-based platform (UroNav, Philips/In Vivo Corp, Gainesville, FL, USA). In addition to the systematic 12-core biopsy, at least 2-targeted cores were obtained per target pre-identified on mpMRI by the uroradiologist. Biopsy specimens were evaluated and assigned with Gleason scores (GS) by the pathologists at the respective institutions.
Study data
Patient demographic, clinical characteristics and biopsy outcomes were recorded. Biopsy pathology was categorized into three categories for the purpose of analysis. Low risk disease was defined as GS 6, intermediate risk as GS 7 (3+4 or 4+3), and high risk as GS of 8 or higher. For the purpose of this study, clinically significant (CS) disease was defined as GS ≥ 3+4.
Statistical Analysis
Statistical analysis was performed using STATA version 13.0 (StataCorp LP, College Station, TX USA). Wilcoxon rank sum test was used to compare distribution of continuous variables. Pearson Chi square and Fisher exact test were used to compare proportions of categorical variables. Cancer detection rates from the multi-institutional biopsy naïve cohort (same four institutions, 395 patients) who underwent FBx were calculated to serve as a graphical comparison against prior negative cohort (data unpublished). McNemar’s test was used to compare cancer detection rates between FBx and SBx. Multivariable logistic regression was done to ascertain independent effect of number of prior negative biopsy on cancer detection through FBx and SBx. Statistical significance was defined as two-sided p-value of less than 0.05.
Results
Patient Demographics
Seven-hundred seventy-nine patients (2007 – 2014) from four institutions with a history of one or more negative SBx were included in the study. Median age (IQR) and PSA (IQR) for patients were 63.1 (58.5-68.0) years and 8.5 (5.9-13.1) ng/ml, respectively. The median number of standard and fusion biopsy cores (IQR) were 12 (IQR:12-12) and 4 (IQR:2-6) respectively. Median number (IQR, range) of prior negative biopsies were 2 (1-3, 1-16). Table 1 summarizes the patient characteristics and biopsy results.
Table 1.
Patient Characteristics and Biopsy Gleason Score (GS) of Systematic Biopsy (SBx) and Fusion Biopsy (FBx).
| Patient Characteristics and Biopsy Results | |
|---|---|
| Median Age in years (IQR) | 63.1 (58.5–68.0) |
| Median PSA in ng/dl (IQR) | 8.5 (5.9–13.1) |
| Positive Family History (%) | 199 (26.3) |
| Median Prostate Volume in mL (IQR) | 59.0 (42.0–82.0) |
| Abnormal DRE (%) | 34 (4.9) |
| Race (%) | |
| Caucasian | 597 (77.7) |
| African American | 119 (15.5) |
| Other | 52 (6.8) |
| Prior Negative Biopsy (%) | |
| One | 278 (36.2) |
| Two | 252 (32.8) |
| Three | 145 (18.9) |
| Four | 55 (7.2) |
| Five or more | 39 (5.1) |
| MRI Suspicion Score (%) | |
| Three and below | 530 (69.1) |
| Four | 106 (13.8) |
| Five | 131 (17.1) |
| Median Number of Biopsy Cores (IQR) | |
| Systematic Bx | 12 (12–12) |
| Targeted Bx | 4 (2–6) |
| Biopsy Results | Systematic Bx | Targeted Bx |
|---|---|---|
| Benign (%) | 514 (66.0) | 511 (65.6) |
| GS 3+3 (%) | 118 (15.2) | 63 (8.1) |
| GS 3+4 (%) | 63 (8.1) | 82 (10.5) |
| GS 4+3 (%) | 25 (3.2) | 37 (4.8) |
| GS 4+4 (%) | 35 (4.5) | 53 (6.8) |
| GS 4+5 (%) | 19 (2.4) | 28 (3.6) |
| GS 5+4 (%) | 3 (0.4) | 3 (0.4) |
| GS 5+5 (%) | 2 (0.3) | 2 (0.3) |
Cancer Detection Rate
Total CDR in the cohort was 44.4% (346/779 patients). There was no difference in overall CDR between FBx and SBx (p=0.75) (Figure 1A). Total CS CDR was 30.7% (239/779 patients), with FBx detecting 26.3% (205/779) of the patients and SBx diagnosing an additional 4.4% (34/779) of patients (p<0.001). Furthermore, of all cancers detected by each modality, FBx detected a higher proportion of CS cancer compared to SBx (One negative biopsy: 75 versus 50%, p<0.001, 2-3 negative biopsies: 76 versus 61%, p =0.006, 4 or more negative biopsies: 84 versus 52%, p=0.006) (Figure 1B). As such, SBx added a relatively small diagnostic value to FBx for detecting CS disease (One negative biopsy 3.5%, 2-3 negative biopsies 5%, 4 or more negative biopsies: 1%) (Figure 2). Also, FBx upgraded patients from a benign or low risk cancer category (GS ≤6) to intermediate or high-risk category (GS >6) relative to SBx more often than SBx upgraded FBx (Table 2).
Figure 1. Performance comparison of Systematic Biopsy (SBx), Fusion Biopsy (FBx) and Combined Biopsy (SBx plus FBx) for the Detection of Prostate Cancer (PCa) as a Function of Number of Prior Negative Biopsy Sessions.
Overall and CS PCa detection rates were plotted by the number of prior negative biopsy sessions stratified in 3 categories (Figure 1A-B). CDRs from the multi-institutional biopsy naïve cohort (395 patients) who underwent FBx were calculated to serve as a graphical comparison against the prior negative cohort.
A. Performance comparison of Systematic Biopsy (SBx), Fusion Biopsy (FBx) and Combined Biopsy (SBx plus FBx) for detecting all prostate cancers as a function of the number of prior biopsy sessions.
B. Performance comparison of Systematic Biopsy (SBx), Fusion Biopsy (FBx) and Combined Biopsy (SBx plus FBx) for detecting clinically significant (CS) PCa (defined as Gleason Score (GS) ≥ 3+4 =7) as a function of the number of prior biopsy sessions.
Figure 2.
Additional value of Systematic Biopsy (SBx) to Fusion Biopsy (FBx) in the Detection of Clinically Significant (CS) Prostate Cancer (PCa) as a Function of the Number of Prior Negative Biopsy Sessions.
Table 2. Comparison of Pathology From Systematic Biopsy (SBx) and Fusion Biopsy (FBx) for Prostate Cancer.
A. Pathologic outcomes per individual of FBx compared with SBx for entire cohort. B. Pathologic outcomes per individual of FBx compared with SBx for patient with one prior negative biopsy. C. Pathologic outcomes per individual of FBx compared with SBx for patient with two or three prior negative biopsies. D. Pathologic outcomes per individual of FBx compared with SBx for patient with four or more negative biopsy.
| A. | |||||
|---|---|---|---|---|---|
| Systematic Biopsy Results | |||||
| Fusion Biopsy results | Benign | Low risk | Intermediate risk | High risk | Total |
| Benign | 433 | 53 | 21 | 4 | 511 |
| Low risk | 22 | 32 | 9 | 0 | 63 |
| Intermediate risk | 38 | 29 | 42 | 10 | 119 |
| High risk | 21 | 4 | 16 | 45 | 86 |
| Total | 514 | 118 | 88 | 59 | 779 |
| B. | |||||
|---|---|---|---|---|---|
| Systematic Biopsy Results | |||||
| Fusion Biopsy results | Benign | Low risk | Intermediate risk | High risk | Total |
| Benign | 152 | 23 | 4 | 1 | 180 |
| Low risk | 9 | 11 | 5 | 0 | 25 |
| Intermediate risk | 9 | 16 | 19 | 3 | 47 |
| High risk | 6 | 1 | 5 | 14 | 26 |
| Total | 176 | 51 | 33 | 18 | 278 |
| C. | |||||
|---|---|---|---|---|---|
| Systematic Biopsy Results | |||||
| Fusion Biopsy results | Benign | Low risk | Intermediate risk | High risk | Total |
| Benign | 222 | 27 | 15 | 2 | 266 |
| Low risk | 12 | 15 | 4 | 0 | 31 |
| Intermediate risk | 20 | 9 | 22 | 5 | 56 |
| High risk | 10 | 2 | 5 | 27 | 44 |
| Total | 264 | 53 | 46 | 34 | 397 |
| D. | |||||
|---|---|---|---|---|---|
| Systematic Biopsy Results | |||||
| Fusion Biopsy results | Benign | Low risk | Intermediate risk | High risk | Total |
| Benign | 53 | 3 | 1 | 0 | 57 |
| Low risk | 1 | 5 | 0 | 0 | 6 |
| Intermediate risk | 8 | 4 | 1 | 2 | 15 |
| High risk | 5 | 1 | 6 | 4 | 16 |
| Total | 67 | 13 | 8 | 6 | 94 |
Green shading indicates patients in whom FBx upgraded prostate cancer risk category in relation to SBx. Dark green indicates cases in which the upgrade was to an intermediate-or high-risk category. Orange shading indicates patients in whom SBx upgraded prostate cancer risk category in relation to FBx. Dark orange indicates cases in which the upgrade was to an intermediate- or high-risk category.
Predictors of Cancer Detection
On multivariable analysis, after adjusting for age, PSA, race, DRE findings, prostate volume, positive family history, and highest MRI suspicion scores, the number of prior negative biopsies remained a significant negative predictor of cancer detection by SBx (Table 3). After adjusting for all confounders, there was a 24% decrease in the detection of CS cancer by SBx with each prior negative biopsy session increase (p=0.006). However, no statistically significant decline in the CS CDR was found on FBx with increases in the number of prior negative biopsy sessions (p=0.151).
Table 3.
Prognostic Factor Analysis for the Detection of Clinically Significant (CS, defined as Gleason Score (GS) ≥ 3+4=7) and Total Prostate Cancer (PCa) Detection on Systematic and Fusion Biopsy (SBx and FBx, respectively).
| Systematic Bx | Targeted Bx | |||||||
|---|---|---|---|---|---|---|---|---|
| Detection of Clinically Significant Cancer | Detection of All Cancers | Detection of Clinically Significant Cancer | Detection of All Cancers | |||||
| Odds Ratio (95% CI) | P-value | Odds Ratio (95% CI) | P-value | Odds Ratio (95% CI) | P-value | Odds Ratio (95% CI) | P-value | |
| Age | 1.11 (1.07–1.15) |
<0.001 | 1.07 (1.04–1.10) |
<0.001 | 1.09 (1.06–1.13) |
<0.001 | 1.07 (1.04–1.12) |
<0.001 |
| Race | ||||||||
| African American | 1.83 (1.03–3.36) |
0.044 | 2.21 (1.35–3.61) |
0.002 | 1.06 (0.57–2.00) |
0.849 | 1.38 (0.80–2.37) |
0.242 |
| Other | 1.16 (0.50–2.72) |
0.753 | 1.37 (0.70–2.73) |
0.359 | 0.88 (0.37–2.11) |
0.771 | 0.88 (0.41–1.87) |
0.736 |
| PSA | 1.03 (1.01–1.05) |
0.001 | 1.04 (1.02–1.06) |
<0.001 | 1.09 (1.06–1.12) |
<0.001 | 1.07 (1.04–1.10) |
<0.001 |
| Prostate Volume | 0.98 (0.98–0.99) |
<0.001 | 0.99 (0.98–0.99) |
<0.001 | 0.96 (0.95–0.97) |
<0.001 | 0.97 (0.96–0.98) |
<0.001 |
| Abnormal DRE | 1.24 (0.45–3.41) |
0.675 | 1.07 (0.44–2.60) |
0.882 | 1.06 (0.35–3.22) |
0.922 | 0.94 (0.35–2.55) |
0.908 |
| Positive Family History | 1.54 (0.94–2.54) |
0.087 | 1.71 (1.14–2.57) |
0.009 | 1.42 (0.87–2.33) |
0.164 | 1.68 (1.09–2.58) |
0.019 |
| Prior Negative Biopsy | 0.76 (0.63–0.92) |
0.006 | 0.75 (0.64–0.88) |
<0.001 | 0.86 (0.69–1.06) |
0.151 | 0.87 (0.72–1.04) |
0.126 |
| MRI Suspicion Score | 1.72 (1.34–2.21) |
<0.001 | 1.40 (1.15–1.70) |
0.001 | 2.26 (1.77–2.91) |
<0.001 | 1.82 (1.47–2.25) |
<0.001 |
Discussion
The diagnostic management of patients with a persistently elevated PSA and prior negative SBx (or biopsies) remains challenging challenge. In an effort to decrease false-negatives, the current paradigm is to resample these patients using repeat SBx or saturation biopsy techniques, although the optimal biopsy approach (transrectal versus transperineal) and number of cores procured is debated13,14,15. However, both techniques have shown diminished value in the repeat biopsy setting16,17. Furthermore, the majority of the cancers detected using these techniques are of low risk, which potentially exposes these patients to the harms of serial biopsy on surveillance or overtreatment18,19. The evidence is mounting that FBx may provide a more precise method to detect CS lesions in patients who have had a prior negative SBx, but continue to have suspicion of disease.
Our multi-institutional cohort with at least one prior negative biopsy sessions revealed no difference in the overall CDR between the two modalities (44.4%). However, within each prior negative biopsy group, a significantly higher proportion of cancers detected by FBx were CS compared to SBx (Figure 1). This is similar to a study of 161 patients with prior negative SBx conducted by Mendhiratta et al which demonstrated similar results, with a comparable overall CDR and also with higher CS cancer detection by FBx compared to SBx20. This increased efficacy for the detection of CS disease by repeat FBx compared to repeat SBx was also described by Sonn et al in their single center experience1. In their study, the targeted cores discovered 1.4 times the number of CS PCa. However, only 15% as many insignificant cancers were found using FBx when compared to SBx. Similarly, Arsov et al performed a multi-institutional study that revealed that SBx required three times the number of cores to detect one CS cancer when compared to FBx (55 versus 19)21. Our multi-instititional study provides additional evidence that FBx, in a prior negative biopsy setting, maximizes CS cancer detection while lowering detection of clinically insignificant cancers.
One reason for the higher CS CDR of FBx compared to SBx is that mpMRI, on which FBx depends, is optimized for the detection of CS disease. This gives the FBx operator a greater ability to visualize and target CS lesions using FBx as opposed to blindly sampling the gland using SBx. As such, these greater capabilities allow one to target traditionally undersampled regions of the gland outside of the traditional SBx template22. Therefore, it is not surprising that FBx detects a greater number of patients with CS disease and has a greater efficacy when compared to SBx.
In our study, the odds of identifying CS cancer on SBx was inversely related to the number of prior negative biopsies a patient had received. Each additional prior negative biopsy was associated with a 24% decrease in the detection of CS disease using SBx (p=0.006). Studies conducted prior to the mpMRI era demonstrated similar results. In a study of 2,526 men, Roehl et al found the yield of SBx on the first, second, third and fourth repeat biopsy to be 17%, 14%, 11% and 9% respectively6. The majority of the cancers diagnosed were GS 6 or below. Similarly, another study in 1,051 men demonstrated that at first repeat biopsy, cancer was detected in only 10% of men, while a second repeat biopsy found cancer in only 5% of men23. Moreover, first, second and subsequent repeat transperineal saturation biopsy has also been shown to have decreasing cancer detection rate of 55.5%, 41.7% and 34.4% respectively, with only half of the lesions detecting greater than GS 624, 25. On the other hand, the diagnostic yield of FBx in our study was independent of the number of prior negatives biopsies sessions a patient had undergone (p=0.151). Also, the proportion of CS disease detected improved with each increasing number of prior negative biopsies. Therefore, CS cancer detection via combination biopsy (SBx plus FBx) was essentially a reflection of the FBx cancer detection rate, with SBx adding a relatively small diagnostic value to FBx for detecting CS disease (Figure 2). This is highlighted by consensus statement from AUA and SAR which recognizes that the prostate MpMRI and targeted biopsies “facilitate the detection of clinically significant disease over standardized repeat biopsy” in repeat biopsy settings and should be the recommended approach if prostate MpMRI is available26,27.
Limitations of our study include the potential for selection bias associated with the retrospective nature of the study. Furthermore, although a clear and precise protocol was adhered to at each institution, some inherent bias exists by the very nature of the study being multi-institutional. For instance, the majority of the data was collected prior to PIRADSv2 was released. Although all institutions used a five-point Likert system, which was similar to the validated NIH suspicion score, the unavailability of a PIRADS scoring system may have introduced some variability in the radiologist’s readings at each institution28. However, all FBx were performed by experienced urologists trained in FBx and all MRIs were interpreted by experienced uroradiologists in academic settings, therefore reducing interinstitutional variability. However, this may positively skew our results compared to a community setting, which may not achieve the same diagnostic yield. Finally, it has been reported that a small percentage of patients with clinical suspicion of prostate cancer, but negative mpMRI harbor CS disease29. As such, our inclusion criteria of a suspicious area on mpMRI may have biased the findings in favor of FBx. Despite these limitations, we believe that our interpretation of the increased efficacy of fusion biopsy in this prior-negative systematic biopsy population is still valid and achieves the objectives of the study.
Conclusion
The results from our large, multi-institutional study demonstrate that FBx detects more CS disease in patients with prior negative biopsies and outperforms SBx beginning with patients with only one prior negative biopsy. Notably, we also show that the greater performance of FBx relative to SBx for detecting CS disease only increases with increasing number of prior negative SBx. This study provides additional strong evidence that repeat SBx alone in patients with previous negative biopsies will be hindered by lower yields and FBx should be used concurrently in these patients.
Footnotes
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