Safety and efficacy of guided biopsy

Chapter 42

Safety and efficacy of guided biopsy Miguel A. Bergero1 and Pablo F. Martinez2 1

Urology, Sanatorio Privado San Geronimo, Santa Fe, Argentina; 2Urology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina

Introduction Prostate cancer (PC) is the most common cancer in men [1]. The introduction of prostate-specific antigen (PSA) testing led to an increase in diagnosis, with the disadvantage of overdetection and overtreatment of clinically insignificant prostate cancer (ISPC) [2]. Transrectal ultrasoundeguided (TRUS) biopsy suffers from low sensitivity and specificity for prostate cancer detection (PCD) or clinically significant prostate cancer (SPC) detection [3]. Increased number of biopsies (e.g., saturation biopsies), or combined biopsies with new markers (e.g., PCA 3), have not solved these problems either [4,5]. Multiparametric magnetic resonance imaging (MP-MRI) look more reliable for PCD [6,7]. Several strategies have been developed for targeted biopsy (TB) of prostate lesions identified on MRI, and PC and SPC detection rates are higher. Furthermore, morbidity is lower with these procedures than with TRUS. MRI-guided biopsy (MRGB) includes (1) in-bore MRI-targeted biopsy (MRI-TB), which is performed during MRI scan, using real-time image guidance; (2) MRI-TRUS fusionetargeted biopsy (FUSTB), where software is used to perform MRI and TRUS image fusion, improving accuracy; and (3) cognitive registration TRUS-targeted biopsy (COG-TB), where an MRI lesion is cognitively targeted using TRUS guidance [8,9].

Standard prostate biopsy TRUS is the mainstay of PC diagnosis [3]. Although it allows real-time visualization of the prostate, it is considered to be unreliable, due to the inability of gray-scale ultrasonography to distinguish PC from benign tissue [10]. Thus, approximately 30% of PC is missed, principally located either in the lateroanterior part of the peripheral zone (PZ), in the anterior part of the transitional zone (TZ), or in the anterior fibromuscular stroma (AFMS) [11,12].

Sextant biopsy schemes have been all but abandoned and extended 12-core biopsy protocols are currently recommended. Although these biopsy schemes have led to increased PCD, they have also resulted in increased indolent cancer detection; consequently, up to 50% of the tumors detected are small and well differentiated [8]. Overdiagnosis has led to the overtreatment, as suggested by the results of the European Randomized Study of Screening for Prostate Cancer [2]. In addition, the number of unnecessary biopsies has increased, along with the morbidity associated with the procedure [13]. BocconGibod et al. [14] compared prostate biopsy with radical prostatectomy (RP) specimens and observed that 42% of the patients had a PC volume <0.5 mL, and 29% exhibited ISPC (Gleason score [GS]
6 or volume <0.5 mL). In contrast, GS 4 was ignored by prostate biopsy in 50% of the cases, thereby demonstrating that biopsy also underdiagnoses SPC. These results were correlated with the 36% GS upgrading, observed by Epstein in RP specimens [15]. RP specimens from patients who underwent surgery during active surveillance also showed 20%e45% GS upgrading [2,16,17].

Saturation biopsy Jones et al. [18] observed no statistically significant difference between saturation and standard biopsies (44.5% vs. 52%). Descazeaud et al. [19] also reported that PCD was similar. Lane et al. [20] reported a high PCD rate on a second biopsy, despite initial saturation biopsy strategy. Up to one in four patients showed evidence of PC on a second biopsy. Delongchamps et al. [21] evaluated a saturation biopsy scheme on autopsied prostate glands, showing no increase in PCD rate over a less extensive scheme. Saturation biopsies might not only miss PC but also overestimate final GS on whole-mount analysis.

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432 PART | II Precision medicine for practitioners

Transperineal biopsy In a prospective study conducted by Emiliozzi et al. [22], PC was detected in 43 of 107 patients; 38% of the patients were assessed using transperineal (TP) 6-core approach and 32% using TRUS 6-core approach. Of the 43 PC diagnosed, 95% were found with TP and 79% with TRUS (P ¼ 0.012) [22]. In a different study, Kawakami et al. [23] showed that there was no statistical difference in PCD rate (86% vs. 82%, P ¼ 0.51) or in the characteristics of PC detected using the TP 14-core approach and the TRUS 12core approach. A recent metaanalysis by Xue et al. [24] confirmed no significant difference in PCD between these approaches. However, combining the two techniques so as to saturate the whole prostate may optimize PCD, as demonstrated by Kawakami et al. [23].

MRI-guided versus standard prostate biopsy in naı¨ve patients Accumulated data regarding TB in overall PCD has been dissimilar [25]. In most publications, overall PCD with MRGB was similar to TRUS [26e32]. A metaanalysis by Wegelin et al. [33], comparing three different techniques for MRI-targeted prostate biopsies, found no difference between MRGB and TRUS for overall PCD. However, in a randomized prospective study, Porpiglia et al. [34] reported superiority for MRGB, compared with TRUS, in overall PCD (50.5% vs. 29.5% [P ¼ 0.002]). Pokorny et al. [8] observed a marked difference in PCD with MRGB (70%) versus TRUS (56.5%), with excellent sensitivity (SN [92%]), specificity (SP [97%]), positive predictive value (PPV [92%]), and negative predictive value (NPV [97%]). Panebianco et al. [11] also observed that MRGB performed better in detecting PC (73%) than TRUS (38%). However, when the percentage of positive cores was reviewed in a different series, it was observed that TB allowed an equal or higher number of PC to be diagnosed, with fewer biopsies. The same was seen when assessing the mean maximum cancer core length. This was recently confirmed by Kasivisvanathan et al. [35], in a well-designed study.

MRGB versus standard prostate biopsy in naı¨ve patients The definition of SPC varies widely, but most use either Harnden or Epstein criteria [36,37]. Haffner’s study demonstrated that MRGB was more accurate in detecting SPC than TRUS (P¼ <0.001), with a diagnostic accuracy of 0.98 under the ROC curve. The study also found that PC that was not detected by TB was primarily indolent (80%) [26]. Likewise, Mendhiratta et al. [30] observed that 83%

of PC detected by systematic biopsy, but not by TB, was clinically indolent. Another randomized trial was reported as a negative study, showing no difference in the detection of SPC between MRGB and TRUS. Nevertheless, it did demonstrate that MRI can play a role in the visualization of SPC. Of all the biopsy-proven SPC occurring in the MRI group, 87% were detected by TB. Of the 29 MRI-detected lesions with a PI-RADS score of 4 or 5, 28 (97%) were SPC confirmed by TB [31]. However, in a recent prospective, multicenter, paired-cohort study, that used a template prostate mapping biopsy as a reference test, Ahmed et al. [6] showed that for the correct diagnosis of SPC, the best-case scenario might lead to 102 (18%) more cases, of clinically significant cancer being detected in 576 men, compared with the standard pathway of TRUS biopsy. Additionally, Mozer et al. [28] observed that the proportion of cores positive for SPC was significantly higher, with the targeted-core protocol (31%) than with the extended 12-core protocol (7.5%), and the median number of cores taken per diagnosis of SPC was significantly higher for the extended 12-core protocol (X ¼ 12 vs. X ¼ 2) (Table 42.1).

MRGB versus standard prostate biopsy in patients with repeat negative biopsies In most studies involving extended 12-core schemes, PC was detected in around 10%e23% of patients on a second biopsy. Furthermore, repeat random biopsies (RBs), in patients with persistently suspicious PC, showed gradually decreasing PCD as the number of biopsies increased [38]. The prostate saturation biopsy schemes were initially recommended for patients who showed a rising level of PSA, despite previous negative prostate biopsies, but new results based on the true prevalence suggest that approximately 40% of PC might remain undetected, regardless of the number of cores taken. In addition, saturation biopsies can be associated not only with increased patient morbidity but also with the risk of indolent cancer detection [39]. In a prospective, randomized, single-center study, Sciarra et al. [38] observed that MRGB (45.5%) detected more PC than TRUS (24.5%), in patients undergoing a second biopsy. Using a matched multisession TRUS population from his institution’s database for comparison, Hambrock et al. [12] reported that cancer detection rate was significantly higher with MRGB (59%) than with TRUS (22%). Just as in these studies, Schoots et al. [40] found in a metaanalysis that MRGB improved overall PC detection, in men with a previous negative biopsy, with a relative SN of 1.62.

TABLE 42.1 MRI-guided biopsy (MRGB) in naı¨ve patients. PCD characteristics Patients and methods

Disease significance

Haffner 2011

N:555 RB versus TB Nonrandomized trial

ISPC Epstein criteria

Delongchamps 2013

N:133 RB versus TB Nonrandomized trial

Pokorny 2014

PCD-RB

TB modalities

MRI lesions

PCDD

PC

SPC

1.5T WEC T2WT1WDCE No PIRADS

COG-TB

351

54%

52%

Diagnostic accuracy 0.88

ISPC GS
6 MCCL <5 mm

1.5T EC T2WDWIDCE No PIRADS

FUS-TB UrostationÒ

82

33%

14%

N:223 RB versus TB Nonrandomized trial

ISPC GS
6

3T WCE T2WDWIDCE PIRADS

MRI-TB

142

56.5%

Quentin 2014

N:128 RB versus TB Nonrandomized trial

SPC GS  6 MCCL >5 mm

3T WCE T2WDWIDCE PIRADS

MRI-TB

329

Mozer 2015

N:152 RB versus TB Nonrandomized trial

SPC 1 NPC: GS 3 þ 4 or GS 6  4 mm

1.5T WCE T2WDWIDCE No PIRADS

FUS-TB UrostationÒ

Peltier 2015

N:110 RB versus TB Nonrandomized trial

SPC GS  6 MCCL >6 mm >2 NPC

3T EC T2WDWIDCE No PIRADS

FUS-TB UrostationÒ

175

Mendhiratta 2015

N:382 RB versus TB Nonrandomized trial

SPC GS  7

3TEC T2WDWIDCE No PIRADS

FUS-TB ArtermisÒ

382

Author

MRI

61%

54%

PCD-TB ISPC

PC

SPC

44%

Diagnostic accuracy 0.98

ISPC

7%

47%

20%

3%

63%

37.3%

70%

94%

6%

53%

42%

11%

53%

45.5.%

8%

56.5%

37%

20%

54%

43.5%

10.5%

54.5%

29%

16%

48%

46.5%

5.5%

49%

27%

22.5%

43.5%

31%

13%

PCD-MRI lesions

Highly suspicious MRI 86% PCD

Highly suspicious MRI 89% PCD

Highly suspicious MRI 86% PCD

NPC RB

PPC TB

RB

TB

Comments

4.7 MCCL

5.6 MCCL

Detection accuracy of SPC was higher with TB TB detected 16% more 4/ 5-grade cases PPC > TB**

10.5%

30%

SPC > TB**

15%

56.5%

33%

61%

SPC > TB** TB decreased the diagnosis of ISPC by 89.5%

14.4%

35.5%

25%

65%

NPC > TB** PPC > TB**

7.5% SPC**

31% SPC**

4 MCCL**

8 MCCL**

SPCD > TB NPP > TB** PPC > TB**

10% SPC

29% SPC

SPCD > TB** PPC > TB**

SPCD > TB ISPCD < TB** MRGB missed 83% of ISPC

Continued

TABLE 42.1 MRI-guided biopsy (MRGB) in naı¨ve patients.dcont’d PCD characteristics Patients and

Disease

TB

MRI

Author

methods

significance

MRI

modalities

lesions

Panebianco 2014

N: 1140 RB versus TB Nonmulticentric randomized trial

Only Gleason informed

3T EC T2W, DWIDCE PIRADS

COG-TB

Baco 2015

N:175 RB versus TB Nonmulticentric randomized trial

SPC GS 6  5 mm GS 7

1.5T WEC T2WDWI PIRADS

Tonttila 2015

N:103 RB versus TB Nonmulticentric randomized trial

Only Gleason informed

Kasivisvanathan 2018 PRECISION

N:500 RB versus TB Multicentric randomized trial

SPC GS  7

PCD-RB PCDD

PCD-TB

NPC

PCD-MRI RB

PPC

PC

SPC

ISPC

PC

SPC

ISPC

lesions

440

38%

37%

1%

73%

72%

1%

T2W þ DCE þ DWI 97% accuracy of PCD

PCD > TB SPCD > TB MP-MRI was unable to detect 96% of ISPC smaller than 0.5 cm3

FUS-TB UrostationÒ

63

54%

49.5%

4.5%

56%

38.5%

21%

Highly suspicious MRI 97% PCD

No difference in PCD and SPCD**

3T WEC T2WDWIDCEDC No PIRADS

COG-TB

40

57%

45%

15%

51%

42.5%

9.5%

Highly suspicious MRI 95% PCD

1.5T/3T WEC/ WERC T2WDWIDCE PIRADS

FUS-TB

175

48%

26%

22%

47%

38%

9%

Highly suspicious MRI 83% SPCD

18%

TB

44%

RB

TB

Comments

4 mm

5 mm

No difference in PCD and SPCD

7.8 mm

6.5 mm

SPCD > TB** ISPCD < TB**

Abbreviations: **, statistical significance; CB, combined biopsy (RB þ TB); EC, endorectal coil; EM, electromagnetic tracking; MCCL, maximum cancer core length; NPC, number of positive cores; PCDD, overall PCD (RB þ TB); PPC, proportion of positive cores; RB, random biopsy; TB, targeted biopsy; TP, transperineal biopsy; WEC, without EC.

Safety and efficacy of guided biopsy Chapter | 42

Most studies show a significantly higher detection rate of SPC and a lower detection rate of ISPC, by MRGB over TRUS. Thus, Sonn et al. [41] found that MRGB detected 91% (21/23) of SPC, while TRUS detected 54% (15/28). Hambrock et al. [12] observed that 37 of 40 (93%) patients who were diagnosed by MRGB had SPC, and all patients who underwent RP had SPC that was previously diagnosed by an MRGB. Salami et al. [42] detected 17% more SPC with MRGB than with TRUS, and the rate of SPC missed with TRUS was higher than with MRGB (21% vs. 4.5%). This was also observed in men undergoing repeat biopsy, in which detection rate for SPC was lower with TRUS (66%) than with MRGB (93%) [12]. This evidence was ratified by Schoots’s metaanalysis [40]. Miyagawa et al. [43] found that the number of cores taken per diagnosis of PC was higher for the extended 12-core protocol than for the targeted-core protocol. This was also observed by Lee et al. [44] and Salami et al. [42] (Table 42.2).

MRI-TRUSetargeted biopsy versus MRItargeted transperineal prostate biopsy Radtke et al. [45] showed that systematic template biopsies missed 21% of SPC and MRGB missed 20%. They concluded that, using transperineal prostate biopsy, MRGB detected at least as much SPC as systematic template biopsies. Pepe et al. [46] compared the accuracy of TRUSMRGB versus TP-MRGB, with lower detection rate for SPC with TRUS-MRGB (66.7%) than with TP-MRGB (93.3%). SN, SP, PPV, and diagnostic accuracy of TPMRGB versus TRUS-MRGB were 97.2% versus 66.7%, 78.2% versus 71.2%, 59% versus 42.1%, 97.2% versus 87.5%, and 70% versus 57.5%, respectively. Recently, MPMRI in men who required further biopsies, using a template prostate mapping biopsy, could be used to safely avoid a repeat biopsy in 14% of the cases, while detecting 97% of the SPC. SN, SP, NPV, and PPV were 80.6%, 68.5%, 83.3%, and 64.3%, respectively, when the 5-point Likert scale response for SPC is “likely” or “highly likely.”(6).

Standard prostate biopsy plus MRGB Siddiqui et al. [47] showed that adding standard biopsy to TB led to 103 more cases of PC (22%), 83% of which were low risk, while only 5% were high risk. MRGB diagnosed 30% more SPC (173 vs. 122 [P¼ <0.001]) and 17% less ISPC (213 vs. 258 [P¼ <0.001]) than TRUS. By contrast, Filson et al. [48] reported that, in patients with a suspicious MRI, MRGB plus TRUS detected not only more PC but also more SPC than each one separately (378 vs. 303 vs. 250 [P¼ <0.001]). MRGB alone detected more SPC than TRUS, and less ISPC (131) than CB (204) and TRUS (208).

435

Comparing three different techniques for MRGB Puech et al. [49] published the first paper that compared FUS-TB with COG-TB, finding no difference in PCD and SPCD rates. Wysock et al. [50] also compared both techniques and observed that PCD and SPCD rates were higher with FUS-TB, mainly in lesions that were highly suspicious for cancer. Delongchamps et al. [51] used conditional logistic regression for FUS-TB, COG-TB, and TRUS to detect PC. FUS-TB performed better than standard biopsy in overall cancer detection, while COG-TB showed a poor performance. Probability of detecting PC that had not been detected with TRUS was significantly higher with FUS-TB than with COG-TB. Finally, FUS-TB detected more Gleason pattern >6 than TRUS, while the detection rate with COG-TB was lower. Three MRGB techniques, in patients with prior negative systematic biopsy, revealed comparable detection rates of overall PC (FUS-TB, 49%; COG-TB, 44%; and MRI-TB, 55% [P ¼ .4]); also no significant differences were seen in the detection rates of SPC (FUS-TB, 34%; COG-TB, 33%; and MRI-TB, 33% [P ¼ > 0.9]). The main limitation of the study was a low rate of PI-RADS  3 lesions on MP-MRI, causing underpowering for primary outcome [52]. T2-weighted imaging (T2W), dynamic contrastenhanced (DCE) imaging, magnetic resonance spectroscopic imaging, diffusion weighted imaging, and apparent diffusion coefficient have increased the accuracy of MRI in PC diagnosis. Two or more of these parameters improve PCD (multiparameter MRI/MP-MRI) [53,54]. In 2012, the European Society of Urogenital Radiology (ESUR) developed the Prostate Imaging Reporting and Data System (PI-RADS) classification, which is a scoring system used to standardize prostate MRI reporting. This classification allowed the method to be replicated, and some publications have shown a clinical correlation between a low score and a high probability of benignity. In 2015, ESUR and the American College of Radiology launched the updated PI-RADS V2 (V2: version 2) [55]. In 2003, the Standards for Reporting of Diagnostic Accuracy (STARD) were published, which is a checklist of items aimed at improving the quality of reports. In 2013, a group of experts adapted STARD for MRGB, to improve the quality of reporting as well as facilitate the comparison between TRUS and MRGB [56]. Other studies used a 5-point Likert scale to report the likelihood of the presence of a clinically significant disease. This scoring system was based on the outputs of a consensus group that was convened before the publishing of the PI-RADS MP-MRI reporting consensus, although the two systems have subsequently been found to be similar [6].

TABLE 42.2 MRI-guided biopsy in patients with prior negative biopsy. PCD characteristics Patients and methods

Disease significance

Sciarra 2010

N:180 RB versus TB Randomized trial

Only Gleason informed

1.5T EC MRSIDCE No PIRADS

COG-TB

45

24%

Hambrock 2010

N:68 RB versus TB Nonrandomized trial

ISPC Epstein criteria

3T EC T2WDWIDCE No PIRADS

MRI-TB

114

Miyagawa 2010

N:85 RB versus TB Nonradomized trial

1.5T WEC T2WDWIDCE No PIRADS

FUS-TB Real-time virtual sonography

Lee 2012

N:87 RB versus TB Nonrandomized trial

ISPC Epstein criteria

3T WEC T2WDWI No PIRADS

COG-TB

Vouragnti 2012

N:195 RB versus TB No randomized trial

Only Gleason informed

3 T EC T2WDWIDCE No PIRADS

Sonn 2013

N:105 RB versus TB Nonradomized trial

ISPC Epstein criteria

Salami 2015

N:140 RB versus TB Nonrandomized trial

ISPC Epstein criteria

Author

MRI

TB modalities

MRI lesions

PCD-RB PCDD

61%

PC

SPC

PCD-TB

PCD-MRI lesions

NPC

ISPC

PC

SPC

ISPC

10%

49%

28%

18%

22%

59%

54%

40%

53%

9%

32%

53%

4%

29%

14.5%

RB

PPC

TB

RB

TB

APC

MRSI þ DCE 91% PCD

PCD > TB SPCD > TB

4.5%

18%

82

52.9%

10%

FUS-TB EM tracking sensor

195

37.5%

23%

5%

18%

29%

11%

18%

Highly suspicious MRI 67% PCD

3T WEC T2WDWIDCE No PIRADS

FUS-TB ArtemisÒ

164

34%

27%

14%

12%

24%

20%

2%

Highly suspicious MRI 88% PCD

3T EC T2WDWIDCE No PIRADS

FUS-TB UroNavÒ

140

65%

48%

31%

18%

52%

48%

4%

Highly suspicious MRI 92% PCD

Comments

68%

PCD > TB NPB > TB**

16.5%

14%

55%

PCD > TB**

39%

PCD > TB

59%

SPCD > TB PSAD was a significant predictor of PCD**

44.5%

4.15

6.21

26%

PCD > TB SPCD > TB PSAD was a significant predictor of SPCD**

PCD > TB SPCD > TB**

Abbreviations: **, statistical significance; CB, combined biopsy (RB þ TB); EC, endorectal coil; EM, electromagnetic tracking; MRSI, magnetic resonance spectroscopy imaging; NPC, number of positive cores; PCDD, overall PCD (RB þ TB); PPC, proportion of positive cores; RB, random biopsy; TB, targeted biopsy; TP, transperineal biopsy; WEC, without EC.

Safety and efficacy of guided biopsy Chapter | 42

437

Suspicious lesions as predictors of prostate cancer detection with MRGB

Prostate cancer index lesion with MRGB

Hadaschik et al. [57] noted that the PCD rate was 96% (23/ 24) in those patients who had a highly suspicious lesion. Filson et al. [48] observed PC in 79% of 825 patients who had a suspicious MRI, compared with 21% of 217 patients with a normal MRI. In addition, 80% of patients with a highly suspicious lesion on MRI had PC with a Gleason pattern 7, compared with 24% with a grade-3 region of interest (P < .001). Likewise, Baco et al. [31] observed 87% of PCD in patients with suspicious lesions on MRI, whereas SPC was detected in 97% of a subgroup of patients with PI-RADS 4 or 5. Rais-Bahrami et al. [58] studied the correlation between MP-MRI suspicion score and the presence of PC, informing marked correlation with high-risk disease, with an SP of 0.89 and an NPV of 0.91 under the ROC curve. Also Vourganti et al. [59] observed correlation between the level of suspicion in images and the detection of PC (P ¼ 0.0004) and SPC (P ¼ 0.033). Kasivisvanathan et al. [35] noted that SPC was highest among participants with PI-RADS V2 score of 5 (83%), followed by 4 (60%) and 3 (12%). Conversely, the percentage of men without cancer was highest among participants with a nonsuspicious PIRADS V2.

The index lesion was defined as the highest Gleason score, or the largest tumor volume if Gleason were the same, in order of priority. MRGB currently allows clinicians to direct biopsies to the region of interest, rather than to a random area. Baco et al. [62] noted a 95% (128/135) concordance of the index lesion location between TB and prostatectomy specimens, and a 90% concordance of primary Gleason pattern between TB and prostatectomy specimens. In a study of similar characteristics, Russo [63] observed that 104 of 115 index lesions were correctly diagnosed by MRI, with a sensitivity of 90.4%, including 98/105 clinically significant index lesions with a sensitivity of 93.3%. Porpiglia et al. [64] noted that, in experienced hands, two cores in the middle of the index lesion allow for a 92.5% accuracy. Additionally, Gleason heterogeneity was observed in 12.6% versus 26.4%, for
8 or 8 mm index lesions, respectively, with a prevalence of Gleason pattern 4 in the center of the target. Similarly, Radtke et al. [65] showed that MRI detected 110 of 120 (92%) index lesions, and that 107 (89%) index lesions harbored SPC. However, this author noted that TB (two cores per lesion) alone diagnosed 96 of 120 (80%) index lesions, standard biopsy alone diagnosed 110 of 120 (92%), and combined standard biopsy and TB detected 115 of 120 (96%). Combined MRGB and standard biopsy detected 97% of all SPC lesions, yielding better results than MRGB or standard biopsy separately.

PSA as predictor of prostate cancer detection with MRGB Vourganti et al. [59] showed that prostate volume was larger (54 vs. 71 mL, p: 0.0006), PSA was higher (18.7 vs. 11.2 ng/mL [P ¼ 0.0005]), and PSA density (PSAD) was greater (0.38 vs. 0.16 ng/ml2 [P¼ <0.001]), in SPC; these variables also had a correlation with SPC detection. In multivariate analysis, only PSAD remained a significant predictor (P ¼ 0.0026). SPC cut-off value was less than 0.15 ng/ml2, as suggested in the National Comprehensive Cancer Network guidelines (nccn.org/professionals/physician_gls/default/aspx). Panebianco et al. [60] evaluated the probability of any PC during follow-up of negative MRI, either in naïve patients or with previous biopsy, and found that PSA and PSAD were both independent predictors of subsequent SPC diagnosis, with PSAD being the strongest (hazard ratio 7.57). In agreement with this report, Washino et al. [61] demonstrated that equivocal PI-RADS V2 score
3 and PSAD <0.15 ng/ml2 yielded no SPC, and no additional detection of PC on further biopsies.

Prostate cancer detection with MRGB outside of the peripheral zone The mean percentage of anteriorly located cancer in an unselected population is about 20%. Nontargeted strategies to reach these anterior lesions have been less successful, discovering only 2% of PC, as shown by Chon et al. [66]. Hambrock et al. [12] evaluated MRI-TB in 71 patients with a persistently elevated PSA and prior negative TRUS biopsies, underlining that the principal tumor site was the most ventral aspect of TZ in 26 of 46 cases (57%), followed by PZ paramedian region in 9 (20%) and PZ anterior horns in 5 (11%). Salami et al. [42] observed that the anatomical locations of cancer missed by TRUS biopsies but detected by FUS-TB were 4 of 23 (17.5%) in AFMS, 12 of 23 (52.2%) in TZ, and 3 of 23 (13%) in anterior PZ. Lee et al. [44] noted that 32 patients had suspicious anterior lesions

438 PART | II Precision medicine for practitioners

on MRI, and TB-detected PC in 19 (59.5%) of them. The same was shown by Vourganti et al. [59]. Pepe et al. [46] observed that TP-MRGB diagnosed not only more PC (93.7%) located in the anterior zone of the prostate, compared with the TRUS-MRGB approach (25%), but also a greater number of SPC (P ¼ 0.001). Radtke et al. [67] showed no difference in the detection of PC and SPC for FUS-TB versus TRUS in the initial biopsy subgroup (P ¼ 0.181 for all PC, P ¼ 0.195 for SPC defined as GS  3 þ 4, and P ¼ 0.661 for GS  4 þ 3). However, in the repeat-biopsy subgroup, FUS-TB performed significantly better than TRUS (P ¼ 0.004 for GS  3 þ 4, and P ¼ 0.02 for GS  4 þ 3).

Prostate cancer upgrading with MRGB Siddiqui et al. [68] remarked that MRGB contributed to improving the Gleason score in 32% of cases. In addition, MRGB detected 67% more Gleason score 4 þ 3, and missed 36% of cases of Gleason score 3 þ 4 than TRUS, thus reducing the detection of low-risk PC. Vourganti et al. [59] also showed that MRGB had improved Gleason score in 38% of cases detected by TRUS. According to Porpiglia et al. [69], primary and secondary GSs were determined accurately in 85 (72.6%) and 111 (86% [P ¼ 0.018]) of the cases for the TRUS group, and in 56 (47.9%) and 103 (79.8% [P¼ <0.001]) for the FUS-TB group. The primary GS 4 rates were quite comparable between TRUS and FUSTB (86.7% vs. 86.5%); conversely, for secondary GS 4, FUS-TB showed better performance (59.6% vs. 84.5%). The rate of correctly classified GS was significantly lower for TRUS than for FUS-TB (P¼ <0.001). The rates of pathological GS upgrading were significantly higher for TRUS (39.3%) compared with FUS-TB (7.8% [P¼ <0.001]). Margel et al. [70] evaluated the impact of MP-MRI on PC reclassification among candidates for active surveillance in a prospective cohort study and revealed that approximately one-third of patients on active surveillance improved their GS with a confirmatory MRGB. He also observed a GS reclassification in only 3.5% of cases with a normal MRI. In line with these findings, Walton-Diaz reported [71] not only that 22.4% of the patients had GS  7 on confirmatory MRGB but also that stable findings on MP-MRI were associated with GS stability in patients with GS 6 who were on active surveillance, which could potentially reduce the number of unnecessary biopsies in men undergoing active surveillance. Recently, a randomized trial was reported as a negative study showing no difference in the upgrading rate between TB and RB. However, significant differences in upgrading on TB were seen between sites, likely reflecting different levels of expertise with the TB technique, as highlighted in the limitations of the study [72].

Negative predictive value of MRI and follow-up of negative MRGB Several studies attempted to validate the clinical usefulness of negative MRIs. Villers [73] compared the histopathology results of RP specimens with MRI findings in men with a suspicious area detected by an MRI biopsy and reported an NPV of 85% for foci >0.2 cm3 and an NPV of 95% for foci <0.5 cm3. Girometti [74] reported that MRIs had an NPV of 100%. Similarly, in a prospective cohort study in which patients underwent an MP-MRI, Perdona [75] noted an NPV of 91%. According to Filson [76], MP-MRIs do not have a very high NPV. This author reported the results of RB among men with negative MP-MRIs, observing an NPV of only 54%. In addition, a GS  7 cancer was found in 16% of the cases on biopsy. In a recent metaanalysis that evaluated 48 studies, the median MP-MRI NPV was 82.4% (IQR 69%e92.5%) for overall PC and 88.1% (IQR 85.7% e92.3%) for SPC [77]. Most recently, PROMIS, a paired validating confirmatory multicenter study that assessed the diagnostic accuracy of MP-MRI in PCD, showed an NPV of 89% (83%e94%) [6]. Few studies evaluated the follow-up of patients with a negative biopsy. Itatani [78] performed a retrospective single-institution study, observing an NPV of 89.6% for SPC during a 5-year follow-up. Similar results were noted by Venderink [79], who observed 1.7% (5/300) of SPC detection after a median 41-month follow-up of patients. Panebianco [60] performed a KaplaneMeier analysis to assess any-grade PC and SPC diagnosis-free survival probabilities in patients with a negative MRI; the results showed that, after a 2-year follow-up, any-grade PC and SPC diagnosis-free survival probabilities were 94% for naïve patients and 95% for patients with a previous negative biopsy, respectively. After a 4-year follow-up, anygrade PC diagnosis-free survival probabilities were 84% in naïve patients and 96% in patients with a previous negative biopsy (long-rank P¼ < 0.001). Moreover, SPC diagnosis-free survival after a 4-year follow-up remained unchanged (Table 42.3).

Quality of life and safety of MRGB Kasivisvanathan [35] informed that health-related quality of life 24 h and 30 days after the intervention did not differ significantly between the MRGB group and the TRUS group. The intervention was associated with similar results regarding immediate postintervention discomfort and pain in the two groups. By contrast, Egbers [80] observed that the intensity of pain was significantly shorter and milder after an MRGB compared with TRUS (P ¼ 0.005). The discomfort may have been associated with the use of anesthesia, as Arsov [81] established that patients with a periprostatic nerve block with 2% mepivacaine before

TABLE 42.3 MRI-guided biopsy (MRGB) in naı¨ve patients or with prior negative biopsy or active surveillance. PCD characteristics

Author

Patients and methods

MRI

TB modalities

Disease significance

PCD-RB

MRI lesions

PCDD

101

54.5%

PC

SPC

PCD-TB ISPC

Pinto 2011

N ¼ 101 RB versus TB Nonrandomized trial

3T WEC T2WDWIDCE No PIRADS

FUS-TB EM

Siddiqui 2013

N ¼ 582 RB versus TB Nonrandomized trial

1.5T WCE T2WDCEMRSI No PIRADS

FUS-TB EM

SPC GS  7

582

54%

44%

22.5%

77.5%

Sonn 2013

N ¼ 151 RB versus TB Nonrandomized trial

3T WEC T2WDWIDCE No PIRADS

FUS-TB ArtemisÒ

SPC GS  7

279

56%

45%

21.5%

78.5%

Radtke 2015

N ¼ 294 TP versus TB Nonrandomized trial

3T WEC T2WDWIDCE PIRADS

FUS-TB BiopSeeÒ

SPC GS  7

225

51%

44%

Maxeiner 2015

N ¼ 169 RB versus TB Nonrandomized trial

3T WEC T2WDWI PIRADS

FUS-TB Aplio 500Ò

SPC GS  7

316

42%

16%

Siddiqui 2015

N ¼ 1003 CB versus RB versus TB Nonrandomized trial

3T EC T2WDCEMRSI No PIRADS

FUS-TB UroNavÒ

Low risk GS 6 or GS 3þ4 (<50% PPC or < 33% NPC)

1003

69% 25% SPCD

47%

Filson 2016

N ¼ 825 CB versus RB versus TB Nonrandomized trial

3T WEC T2WDWIDCE No PIRADS

FUS-TB ArtemisÒ

SPC GS  7

825

70.5% 46% SPCD**

PC

SPC

ISPC

PCD-MRI lesions Highly suspicious MRI 89.5% PCD**

55.5%

79%

21%

30%

26%

25.5%

43.5%

35%

65%

35%

24%

76%

38%

87%

26%

88%

46%

25%

52.6%

36.5%

NPC RB

TB

12%

21%

9.2%

Highly suspicious MRI 94% SPC

Highly suspicious MRI 76% PCD

7%

7.5%

12%

RB

TB

NPC > TB

SPCD > TB NPC > TB** 32% of GS upgrading with TB GS upgrading was associated with MRI suspicion score**

47.5%

21%

Comments

3.3 MCCL

5.1 MCCL

SPCD > TB NPCD > TB** PPC > TB**

46%

SPCD > TB TB missed 44% of the ISPC

21%

SPCD > TB TB detected 88% of the SPC

SPCD > TB** CB detected 22% more PC (83% ISPC) TB diagnosed 30% more high-risk PC and 17% fewer low-risk PC than RB

21%

16%

PPC

Highly suspicious MRI 80% SPC**

SPCD > CB** CB detected 20% more SPC. PCD was associated with MRI suspicion score **

Abbreviations: **, statistical significance; CB, combined biopsy (RB þ MRGB); EC, endorectal coil; EM, electromagnetic tracking sensor; MCCL, maximum cancer core length; N, number of patients; NPC, number of cores positive; PCDD, overall PCD (RB þ MRGB); PPC, proportion of cores positive; RB, random biopsy; TB, targeted biopsy; TP, transperineal biopsy; WEC, without EC.

440 PART | II Precision medicine for practitioners

MRGB have significantly lower pain levels compared with those with intrarectal instillation of a 2% lidocaine gel (IBGB) before TRUS. However, the addition of TRUS significantly increases the number of biopsy cores, and MRGB still requires significantly less time in comparison with IB-GB. One of the most frequent complications of TRUS is bleeding. In a systematic review of complications arising from prostate biopsies, hematospermia was the one most frequently (10%e90%) reported after a TRUS [13]. Some authors associated this condition with the number of biopsies performed. For instance, Berger [82] reported hematospermia in 31.8% of cases after 6-core biopsies, 37.4% after 10-core biopsies, and 38.4% after 15-core biopsies (P¼ < 0.001). Egbers [80] observed no difference when comparing MRI-TB with TRUS (36% vs. 33% [P¼ > 0.05]). Another frequent event associated with TRUS is hematuria (20%e80%). Egbers [80] reported hematuria in 51% of cases after an MRGB compared with 79% of cases after a TRUS biopsy (P ¼ 0.006); although minor hematuria is common after a prostate biopsy, significant bleeding requiring hospitalization occurred in less than 1% of cases. Finally, hematochezia had a low incidence after TRUS biopsies and was not related to the number of biopsies performed [83]. In addition, MRGB showed no significant differences with TRUS in terms of incidence and duration. Recently, a PRECISION study noted that bleeding complications were less frequent in the MRGB group than in the TRUS one, including events of hematuria (30% vs. 63%), hematospermia (32% vs. 60%), pain in the site of the procedure (13% vs. 23%), and hematochezia (14% vs. 22%) [35]. Urinary infection is a frequent comorbidity associated with TRUS and hospitalization. According to the Global Prevalence Study of Infections in Urology, 3.1% of patients required hospitalization after a biopsy. But the most potentially life-threatening infectious complication is sepsis [84]. However, other series from North America and Brazil reported lower sepsis rates of 0.6% and 1.7%, respectively [85]. Most reported infectious complications result from Escherichia coli, with high rates of resistance to fluoroquinolones, ampicillin, and sulfamethoxazoletrimethoprim. Fluoroquinolone resistance has increased globally. Various strategies have been explored to reduce infectious complications, such as cleansing the rectum with povidone-iodine before a TRUS biopsy, switching or expanding the antimicrobial regimen, performing rectal swab cultures, using targeted prophylaxis, or applying different biopsy techniques. Based on the data currently available, TP appears to be associated with a lower risk of infectious diseases and hospitalization. While MRGB allows as few as one or two cores to be taken, the most common approach for TB continues to be the transrectal

one as there is slight evidence that it reduces the risk of infections. In a systematic review, only one study reported possible benefits of the transrectal approach, but they were not statistically significant [83]. There is a low risk of acute urinary retention after a standard TRUS biopsy, ranging from 0.2% to 1.7%. Urinary retention is usually transient, and most patients do not require surgery. A risk also exists for short-term worsening of voiding complaints after a TRUS biopsy. Reported rates of dysuria typically range from 6% to 25% [13]. Raaijmakers [86] observed that prostate volume and higher voiding symptoms were associated with risk of urinary retention after a prostate biopsy. Similarly, Zaytoun [87] showed that a larger prostate predicted urinary retention after biopsy (OR: 4.45 [P¼< 0.001]). There is no convincing evidence suggesting that the number of biopsy cores increases the risk of urinary retention; but, based on the data currently available, the reported incidence of acute urinary retention after MRGB is sporadic, from 0% to 1% [83]. Mortality after prostate biopsy is extremely rare, and most deaths reported are the result of a septic shock. However, men who were hospitalized due to infectious complications had a 12-fold higher 30-d mortality rate in comparison to those who were not (95% CI, 8.59e16.80 [P¼ < 0.0001]). Lethal Fournier’s gangrene has also been reported. Bleeding after the procedure is usually selflimiting and rarely a life-threatening complication [83].

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