5. Diagnosis and staging – Prostate Cancer

Version 6.2 · October 2021 · AWMF 043/022OL
Leitlinienprogramm Onkologie · Deutsche Krebsgesellschaft · Deutsche Krebshilfe · AWMF

5.1 Punch biopsy of the prostate

5.1 · Consensus-based Recommendation · checked 2018

Before deciding to undergo a biopsy, the patient shall be informed in sufficient time before the procedure by a physician about the potential benefits, risks, and consequences of a prostate biopsy.

Consensus: Consent (95%)

5.2 · Evidence-based Recommendation · modified 2018

a. The punch biopsy shall be performed under transrectal ultrasound guidance.

b. Areas that are suspicious on palpation shall additionally be biopsied under palpation guidance.

c. In imaging procedures, areas suspicious for prostate carcinoma shall be additionally biopsied in a targeted manner.

Recommendation grade

A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht

Level of evidence

(a)

(b+c)

Consensus

Strong consensus (97%)

References

[96] [97] [98] [99] [100] [101]

Evidence tables (1)

5.1 EvT 5.2

5.3 · Evidence-based Recommendation · checked 2018

Usually ten to twelve punch cylinders of tissue shall be taken during the punch biopsy.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 1++
Consensus: Strong consensus (98%)
References: [97] [101] [102] [103]

Evidence tables (1)

5.1 EvT 5.3

5.4 · Evidence-based Recommendation · checked 2018

The punch biopsy shall be performed with antibiotic prophylaxis.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 1+
Consensus: Consent (95%)
References: [104]

Evidence tables (1)

5.1 EvT 5.4

5.5 · Evidence-based Recommendation · modified 2018

Local injected anesthesia should be administered to reduce pain sensation during punch biopsy of the prostate.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 1++
Consensus: Consent (91%)
References: [105] [106] [107]

Evidence tables (1)

5.1 EvT 5.5

5.6 · Evidence-based Recommendation · modified 2018

A repeat biopsy shall be recommended within six months for the following constellations of findings:

• extensive high-grade PIN (detection in at least 4 tissue samples);

• atypical small acinar proliferation (ASAP);

• isolated intraductal carcinoma of the prostate (IDC-P);

• suspicious PSA level or PSA progression.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2+
Consensus: Strong consensus (98%)
References: [108] [109] [110]

5.7 · Consensus-based Recommendation · checked 2018

Before any further biopsy is performed, the physician and patient shall weigh up their potential benefits, risks, and consequences.

Consensus: Strong consensus (100%)

Re: Recommendation 5.1

This is in line with good clinical practice. Prostate biopsy is a surgical procedure that can be performed as an inpatient or outpatient procedure. Prior to any surgical procedure, written patient consent is required with patient education provided at that time. This information includes, among other things, the risks of the surgical procedure. Since this is an operation to confirm a suspected clinical and laboratory diagnosis, the potential benefit and limits of the diagnostic measures should be discussed. The explanation includes a discussion of the possible consequences and the resulting treatment options in the event of a positive result. The possibility of a false-negative biopsy result should also be pointed out, and the consequences of this explained.

Re: Recommendation 5.2

Aspects of the rationale:

In patients with an abnormal prostate on palpation, methodologically weak studies indicate higher sensitivity for TRUS-guided biopsy than for digitally guided biopsy [98], [99], [100]. Improved delineation of the prostate by TRUS facilitates systematic tissue sampling from the different anatomical areas of the organ, and allows for simultaneous volume determination.
Since areas of the prostate that are abnormal on palpation may not necessarily be identified on transrectal ultrasound, it may be useful in individual cases to additionally biopsy these areas under palpatory guidance. Particularly during the initial biopsy, areas that are suspicious on palpation can also be biopsied under ultrasound control.
If imaging (e.g., MRI or ultrasound) is used as part of the diagnosis and areas suspicious for prostate cancer are found, this guideline group is of the opinion that a targeted biopsy of these areas can help to increase the reliability of the diagnosis and should therefore be performed accordingly.

Re: Recommendation 5.3

According to the results of the extensive systematic review by Eichler 2005, the number of positive findings increases with the number of punch cylinders taken, with a number of ten to twelve being considered reliable. This led to an identical recommendation also being made in other international guidelines [97], [101]. The prostate punch cylinders obtained should be taken from the regions (APEX, CENTER, and BASE) according to a defined scheme. Likewise, the sampling zone of the prostate (lateral peripheral, middle peripheral, and transitional zones) must be indicated (e.g., schemes according to [102]). The individual punch cylinders are sent in separate specimen tubes. In this way, the samples taken can be precisely assigned later (see chapter 5.4 Pathomorphological examinations).

If the required number of specimens cannot be obtained due to a very small prostate volume, at least six biopsies should be taken.

Re: Recommendation 5.4

The recommendation is based on the results of the systematic review by Bootsma 2008 [104]. This yielded a significantly lower rate of bacteriuria after punch biopsy under antibiotic prophylaxis based on the included studies. The recommendation is made despite bacteriuria being only a surrogate parameter, with no conclusive results available for the more clinically relevant outcomes of fever and urinary tract infection. The studies also typically exclude patients with nonsterile urine or even symptoms of UTI, which should be considered in their interpretation. The decisive factor in formulating a clear recommendation for antibiotic prophylaxis was the favorable risk-benefit ratio of this medication.

Re: Recommendation 5.5

This recommendation is based on the results of several systematic reviews demonstrating a reduction in pain perceived following locally injected anesthesia (e.g., periprostatic block) compared with placebo or local topical anesthesia [105], [106], [107]. Corresponding studies are lacking on analgosedation. However, it can be assumed that there is also an advantage in this case due to the reduction of pain sensation. For reasons of patient safety, however, further aspects must be taken into account. In addition to venous access, the patient must receive a minimum level of monitoring (ECG, blood pressure, pulse oximetry). Emergency equipment must also allow for the possibility of ventilation.

Re: Recommendation 5.6

This recommendation is based on the observation that patients with ASAP (atypical microacinar proliferation) or high-grade PIN (HG prostatic intraepithelial neoplasia) are at high risk for invasive prostate cancer on repeat biopsy. The studies with the largest numbers of patients are listed in the evidence table (see guideline evidence tables document). According to these, 42 to 48% of patients with ASAP in the initial biopsy have invasive prostate carcinoma in the follow-up biopsy [108], [109]. In patients with high-grade PIN, the rate of invasive biopsies was 35 to 47% in two studies from 1995 and 2001 [108], [110]. However, a systematic review including recent literature does not show a significantly higher rate of invasive cancer on follow-up biopsy compared with patients having rebiopsy following a benign diagnosis [111], a median of 24.1% of cases were diagnosed with invasive cancer [111]. The reduction in invasive carcinoma on rebiopsy in recent times has been attributed to the higher number of tissue samples collected at initial biopsy. However, with extensive high-grade PIN (invasive cancer in at least four tissue samples), the risk increases (data from a retrospective case series) to 39%, so rebiopsy is recommended in this case [112].

In patients with signs of both atypia, the risk is also described as significantly increased at 57% [108]. In the case of an isolated intraductal carcinoma of the prostate, the guideline group similarly finds there to be an indication for re-biopsy, as well as in the case of a suspicious PSA value or trend in values.

The interval for control biopsy given in the literature is between six and twelve months.

Re: Recommendation 5.7

See Recommendation 5.1. In addition to the information provided prior to the first biopsy, the lower success rate and the altered significance of the result should be explained before the first (and/or each subsequent rebiopsy). If applicable, the treatment options may also have changed. In addition, further options should be discussed if the biopsy is negative again. An MRI can be performed for further clarification and, if there is further suspicion of a possible cancer, targeted biopsies can be performed on the basis of the MRI imaging, or a further biopsy can be avoided alltogether with (see Recommendation 5.17; in this case, monitoring of the PSA value should be discussed with the patient.

5.2 Primary diagnosis

In the following, the term “primary diagnosis“ refers to all measures that are performed outside of studies until a histologically confirmed primary diagnosis is available.

5.8 · Evidence-based Recommendation · checked 2018

If prostate cancer is suspected, a digital-rectal examination shall be performed.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2++
Consensus: Consent (93%)
References: [113] [114]

Evidence tables (1)

5.2 EvT 5.8

5.9 · Evidence-based Recommendation · modified 2018

Transrectal ultrasound examination can be used as a complementary imaging diagnostic method if it meets the applicable quality requirements.

Recommendation grade: 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
Level of evidence: 1+
to 3 (SIGN)
Consensus: Strong consensus (97%)
References: [115] [116] [117] [118]

Evidence tables (1)

5.1 EvT 5.9

5.10 · Evidence-based Recommendation · checked 2018

Contrast-enhanced ultrasound should not be used for primary diagnosis.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 1+
to 3 (SIGN)
Consensus: Strong consensus (98%)
References: [119] [120] [121] [122] [123] [124] [125]

Evidence tables (1)

5.2 EvT 5.10

5.11 · Evidence-based Recommendation · checked 2018

Ultrasound elastography shall not be used for primary diagnosis.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 1+
to 3 (SIGN)
Consensus: Consent (95%)
References: [126] [127] [128] [129] [130] [131] [132] [133]

Evidence tables (1)

5.2 EvT 5.11

5.12 · Evidence-based Recommendation · checked 2018

Computerized ultrasound (histoscanning) shall not be used for primary diagnosis.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2-
Consensus: Consent (95%)
References: [134] [135]

5.13 · Evidence-based Recommendation · checked 2021

MRI of the prostate shall be performed multiparametrically (mpMRI) according to current quality standards.

(For indication see 5.15 to 5.18.)

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2+
Consensus: Strong consensus (98%)
References: [136] [137] [138]

Evidence tables (1)

Drost_Cochrane_2019_Drost_EurUrol_2020

5.14 · Evidence-based Recommendation · modified 2021

a. The foci which are suspicious for carcinoma as described on mpMRI shall be biopsied in a targeted manner.

(A)

b. In addition to the mpMRI-targeted biopsy, a systematic biopsy should be performed as part of the initial biopsy.

(B)

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2++
Consensus: Strong consensus (100%)
References: [139] [140] [141] [142] [143] [144] [145] [146] [147] [148] [149] [150] [151] [152] [138]

Evidence tables (2)

5.2 EvT 5.14; Drost_Cochrane_2019_Drost_EurUrol_2020

Re: Recommendation 5.8

Despite having low sensitivity, digital rectal examination (DRE) for the primary diagnosis of elevated PSA has a relatively high specificity and a very high negative predictive value. A meta-analysis [113] showed a sensitivity of 59% (51-67%), a specificity of 94% (91-96%), a positive predictive value of 28% (20-36%) and a negative predictive value of 99% (98-99%). As a caveat, not all studies explicitly defined which findings were considered "positive DRE". In addition, DRE findings were only partially compared with histologic findings from prostatectomy specimens, and in other cases only with punch biopsies performed subsequently.

DRE can be easily performed without any equipment by any urologist and is associated with low inconvenience for the patient and low cost. In the case of a suspicious digital-rectal examination, further diagnostic testing (biopsy) are indicated independently of the PSA value (see chapter 4 Early detection).

In clinical practice today, it is not uncommon for the PSA level to be determined first, which can lead to the suspicion of prostate cancer. Regardless of the level of the PSA value, a DRE should be performed as part of early detection (see Early detection chapter). In contrast, DRE is of secondary importance in screening (4.2) [153].

Re: Recommendation 5.9

The test quality parameters of TRUS are comparable to those of DRE, and are therefore limited. Regardless of the limited test quality, simple TRUS can be used for volumetry, and thus can be helpful in evaluating PSA levels; this is especially true for obese patients.

The technical quality standard for TRUS is: use of an ultrasound probe consisting of fixed transducers with an ultrasound frequency of 7.5 MHz. For volumetry, the determination of the length of the prostate in the sagittal plane, as well as the determination of the width and height of the prostate in the transverse plane is performed. The 3-point measurement of the prostate volume can be approximately calculated by applying the following formula (the factor ∏/6 is approximately 0.52): V= length x width x height x ∏/6).

The results from Doppler sonography differed only slightly from those of TRUS. The combination of both techniques does not lead to a relevant improvement in the results (PPW 47%, NPW 69%) [115], [116]. Furthermore, the test quality parameters depend to a significant degree on the investigator [116]. Very good recent results from a small monocentric Asian case series (40 pat., positive predictive value 93.7 %) are not considered to be well transferable to other investigators [154] and have not changed the overall assessment of the method.

Update research (12/2010) on TRUS yielded two retrospective cohort studies [117], [118], in which targeted sampling was performed using combined morphologic criteria in addition to systematic biopsies. An increase in positive predictive values was achieved primarily through improved specificity. Lee et al. [117] achieved a positive predictive value of 83% (in contrast to 52% for systematic biopsy alone) in the presence of the following four malignancy criteria:

Increased blood flow
Irregular boundary
Nodular or cluster abnormality
Extension of the abnormality to the outside of the peripheral zone

These criteria are similar to those described by Tamsel et al. [118] (focal hypo- or hyperechogenic areas, conspicuous border, and poorly-defined areas of altered gray scale).

Since Lee et al. obtained the best results, these malignancy criteria should be used. It has been taken into account that there are no sufficiently good or reliable results for Doppler ultrasound as a single criterion, nor is Doppler ultrasound generally available. The criterion is therefore classified as optional.

Re: Recommendation 5.10

There is a randomized-controlled single-center study [121] as well as several prospective and retrospective case series/cohort studies ([119], [120], [122], [123], [124], [125]. on the use of contrast-enhanced ultrasound (CEUS) and the additional targeted biopsy based on this.

Four of the seven studies were from one institution. The largest evaluation from this center [120] showed no significant differences in test quality parameters retrospectively in 345 screening volunteers (sensitivity 77.1% with CEUS vs. 73.4% without CEUS). The randomized study of 100 patients from this center [121] and the reference standard of biopsy demonstrated a statistically significant advantage of using CEUS (16% carcinomas detected vs. 13% with TRUS alone (p=0.04).

Other studies (44-115 pat.) showed improved sensitivity of 15%-53% with CEUS-targeted biopsies ([119], [122], [123], [125]. Each study noted the higher number of cancer-positive biopsies with CEUS. However, each study also found approximately equal numbers of cancers detected only by systematic biopsy. A European multicenter study (https://clinicaltrials.gov/ct2/show/NCT00911027) was discontinued in spring 2011 because the targeted minimum improvement in test quality was not achieved by using CEUS in the participating centers (according to personal communication from a study participant). Overall, the procedure cannot therefore be routinely recommended as part of primary diagnosis because it is apparent that the positive results from individual centers cannot be reproduced across the board. Centers using the procedure should prospectively demonstrate that they can achieve improved test quality parameters, both statistically and clinically significantly, by applying this approach.

Re: Recommendation 5.11

Regarding the ultrasound-guided procedure of elastography for the diagnosis of prostate cancer, a primary search identified one randomized-controlled trial ([127] n= 351 and seven prospective case series/cohort studies [126], [128], [129], [130], [131], [132], [133]. The randomized-controlled trial using the reference standard of histology from a systematic biopsy of ten specimens did not yield a statistically significant advantage for additional assessment of tissue elasticity and targeted biopsy sampling of abnormal areas. In the elastography group, 40.2% prostate cancers were correctly detected (sensitivity 44.5%), compared with 37.7% in the systematic biopsy-only group (sensitivity 39.5%). The case series and cohort studies show different results regarding the test performance of the method elastography (positive predictive value between 20 % and 87.8 %). The only study with the reference standard of histology from the prostatectomy specimen [132] is a case series. Elastography was performed here after biopsy had already been performed. The results showed a sensitivity of 75.4 % and a diagnostic accuracy of 76 % without any information about a comparative intervention. Due to the negative result of the RCT [127] and the heterogeneous results of the case series and cohort studies, the procedure is not recommended for primary diagnosis.

Re: Recommendation 5.12

A single-center primary study of 29 nonconsecutive patients was identified for computerized ultrasound diagnosis (histoscanning) for prostate cancer. Recruitment took place over 1.5 years. Two publications were found reporting the results [134], [135]. First, with a known diagnosis of prostate cancer, after creating a test set with data from 15 patients, there was a high correlation (r=0.95 p<0.001) of the findings of histoscanning with the prostatectomy specimen on data from 14 patients in terms of tumor characterization (laterality, focality, extracapsular growth). The second publication of the series focuses on the acquisition of a prostate volume up to 50 ml. The studies can be described as exploratory pilot studies. The method is not sufficiently validated for use in primary diagnostics.

Re: Recommendation 5.13

Due to the increasing use of multiparametric MRI (mpMRI) of the prostate, the required quality standards can be precisely defined. Nevertheless, these quality standards are subject to regular changes. The relevant professional societies (DRG and BDR) have issued an updated recommendation for the preparation for, and performance of mpMRI of the prostate (MR prostatography), which defines the current quality standards ([155][156]).

Re: Recommendation 5.14

For explanations regarding targeted biopsy and its combination with systematic biopsy, see Statement 5.15 (initial biopsy) and Recommendation 5.17 (rebiopsy).

5.2.1 Initial biopsy

5.15 · Evidence-based Statement · checked 2021

The majority of study results on mpMRI-guided vs. systematic biopsy vs. a combination of both procedures in previously biopsy-naïve men indicate that mpMRI-guided biopsy detects significant cancers slightly more frequently (in the range of 10%) than systematic biopsy alone. However, significant cancers are missed in mpMRI and targeted biopsy, just as systematic biopsy fails to detect a relevant proportion (in the range of 20%). The combination of an mpMRI-guided targeted approach plus systematic biopsy achieves better detection rates than either method alone.

Level of evidence: 1-
to 2 (SIGN)
Consensus: Consent (90%)
References: [143] [144] [147] [148] [151] [157] [158] [159] [160] [161] [162] [163] [164] [165] [166] [167] [168]

Evidence tables (1)

5.2.1 EvT 5.15

5.16 · Evidence-based Recommendation · modified 2021

a. mpMRI according to current quality standards should be used as part of primary diagnosis.

b. A normal result on mpMRI (PI-RADS <3) carries a residual risk of significant tumors, such that a systematic biopsy should be offered in addition to PSA-based monitoring.

(Expert Consensus)

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 2++
Consensus: Strong consensus (98%)
References: [152] [138]

Evidence tables (1)

Drost_Cochrane_2019_Drost_EurUrol_2020

Re: Statement 5.15 and Recommendation 5.16

Data from systematic reviews and diagnostic studies are available on the diagnostic accuracy of MRI-guided biopsy, systematic biopsy, and a combination of both methods in biopsy-naïve patients with suspected prostate cancer [169][152][138]. Reported outcomes and differences between methods vary according to study design and patient population. For the purposes of the assessment, studies were only considered where they explicitly reported on the detection of clinically significant carcinoma, although it should be noted that the definition of this is not entirely uniform.

Diagnostic studies primarily aim to evaluate diagnostic accuracy. Thus, they cannot answer questions about all-cause mortality because of their inherent end points and the short follow-up period at present. Therefore, the evaluation of benefit of MRI fusion biopsy addresses the following endpoints:

fewer missed clinically relevant prostate cancers and thus earlier detection (and treatment with curative intent)
more accurate histology (with reduction in the upgrade in Gleason score in the prostatectomy specimen) and thus more precise diagnosis (and more adequate therapy).
Reduction in diagnosis of insignificant prostate cancers by MRI fusion biopsy alone (and thus less overtreatment).
Reduction in the number of biopsies with MRI fusion biopsy alone, and thus higher patient acceptance of the method with reduced morbidity.

The Cochrane paper (Drost et al. 2019) examined both randomized and non-randomized prospective studies [138]. As a result, MR-assisted biopsy was shown to detect fewer low-risk prostate cancers and reduce the number of biopsies needed by one-third compared with conventional systematic biopsy, but was shown to detect more significant prostate cancers. These results are relevant to patients as this reduces overdiagnosis and harm from subsequent overtreatment. With regard to the improved detection of clinically significant tumors, differences between biopsy-naïve men and biopsied patients with previously negative results are evident. For the former patients, the benefit of MRI fusion biopsy was not statistically relevant (see table below).

Table 4: Detection rate ratio (Drost et al. 2019)

	Detection rate ratio (pooled) (95% CI) (mixed population)	Detection rate ratio (pooled (95 % CI) (men with previously negative biopsy)	Detection rate ratio (pooled) (95% CI). (biopsy-naïve men)
MRI pathway vs. systematic biopsy	1.12 (1,02-1,23) 25 studies, 6,944 subjects	1,44 (1,19-1,75) 10 studies, 1,564 subjects	1,05 (0,95-1,16) 20 studies, 5,219 subjects
CI=confidence interval

Detection rate ratio (pooled) (95% CI)

(mixed population)

Detection rate ratio (pooled (95 % CI)

(men with previously negative biopsy)

Detection rate ratio (pooled) (95% CI).

(biopsy-naïve men)

MRI pathway vs. systematic biopsy

1.12 (1,02-1,23)

25 studies, 6,944 subjects

1,44 (1,19-1,75)

10 studies, 1,564 subjects

1,05 (0,95-1,16)

20 studies, 5,219 subjects

CI=confidence interval

It should also be noted that either targeted or systematic biopsy alone regularly fail to detect carcinomas [162][163][165][168], with both procedures overlooking different carcinomas. The numerical values of approximately 10% and 20% cited in the statement are from the review by Wegelin et al. [139] and include primary as well as secondary biopsies. In the PROMIS study [168], 10.8% of men with a normal MRI were subsequently found to have prostate cancer on template biopsy; and in another study [144], 16% of men with a normal MRI were found to have clinicallysignificant carcinoma on systematic biopsy. Studies evaluating the detection rates of the combination of MRI-guided targeted approach together with systematic biopsy [144][148][151][170][171] show that this approach is the most meaningful on a reliable basis when compared with the individual procedures.

Ahdoot et al. demonstrated in a patient population with prostatectomy as the reference standard that the combination of both procedures was least likely to result in subsequent tumor upgrading to ISUP Gleason grade group 3 or higher (3.3% vs. 8.7 % for MRI fusion biopsy and 16.6% for systematic TRUS biopsy) [170]. To minimize the influence of targeting errors, lesions that are abnormal on MRI are usually targeted for biopsy at least 2 times [172][173]. PI-RADS 3 findings are biopsied in many cases; in centers with high expertise and internal quality control, and taking into account other clinical factors such as PSA density, monitoring of PI-RADS 3 lesions is also possible as an alternative [174].

In general, the localization of the biopsies taken should be carefully documented (see Chapter 5.4 Pathomorphological examinations). This procedure also allows the distinction between targeted and systematic biopsies, which is important in the context of active surveillance, for example, so that several positive targeted biopsy cylinders do not immediately lead to exclusion from surveillance (see background text to recommendation 6.8).

5.2.2 Rebiopsy

5.17 · Evidence-based Recommendation · modified 2021

a. After negative systematic biopsy without prior mpMRI, if carcinoma is still suspected, imaging by mpMRI shall be performed according to the applicable quality standards.

b. After negative rebiopsy, no further invasive intervention shall be performed if clinical parameters (DRE and PSA) remain unchanged.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2++
Consensus: Strong consensus (100%)
References: [139] [141] [142] [143] [144] [146] [148] [149] [152] [138]

Evidence tables (2)

5.2.2 EvT 5.17; Drost_Cochrane_2019_Drost_EurUrol_2020

5.18 · Evidence-based Recommendation · modified 2021

a. Patients considering Active Surveillance shall be given an mpMRI that meets current quality standards prior to this being indicated.

b. If suspicious areas (PI-RADS 3-5) are seen on mpMRI, they shall be targeted for biopsy.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2++
Consensus: Strong consensus (97%)
References: [175] [152] [138]

Evidence tables (1)

Drost_Cochrane_2019_Drost_EurUrol_2020

5.19 · Evidence-based Recommendation · checked 2018

PET/CT shall not be used for primary diagnosis.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 3
Consensus: Consent (95%)
References: [176]

Evidence tables (1)

5.2.2 EvT 5.19

Re: Recommendation 5.17

Several reviews and the recent meta-analyses by Drost et al. and Kasivisvanathan et al. consistently show that in men with a negative biopsy but who are still suspected to have prostate cancer, imaging with mpMRI followed by targeted biopsy of suspicious areas improves the detection of clinically significant carcinomas, in particular as compared to only repeating systematic biopsy [139][140][142][143][169][152][138].

In summary, based on the available evidence, mpMRI with subsequent targeted biopsy of abnormal findings is now required in cases of negative initial conventional biopsy where there is a suspicion of prostate carcinoma. The extent to which targeted biopsy is combined with systematic biopsy should be decided on a case-by-case basis, as this increases the risk of overdiagnosis. Nomograms can support decision-making [177][178]. A repeat negative re-biopsy result provides a high degree of certainty and allows for a strong recommendation to be made that no further invasive intervention should be performed if clinical parameters remain unchanged. This assumes that the lesion has been hit with certainty. If this is in doubt, an in-bore biopsy should be discussed for PI-RADS 4 or 5 findings [179].

For the indication of systematic biopsy, see also Recommendation 4.6.

Re: Recommendation 5.18

Patients with biopsy-proven prostate cancer and defined parameters indicating a low risk of progression are eligible for Active Surveillance (see Recommendation 6.8). To increase the certainty that no tumor with a higher risk profile was missed in the systematic biopsy, the authors make a strong recommendation for a complementary MRI scan. Analogous to Recommendation 5.14, suspicious areas should be targeted for biopsy. There is promising but not yet definitive evidence on the long-term benefit of this approach (c.f., e.g., [180][181][182][183][184][185]); there is evidence from comparative cohorts that MRI reduces the likelihood of subsequent upgrading and may reduce the number of rebiopsy procedures [186]. The PRECISE criteria [187][188] are recommended for reporting mpMRI in the context of Active Surveillance.

Re: Recommendation 5.19

See background text to Recommendation 5.29.

5.3 Staging

The current UICC classification should be used for staging [189]. The staging of the UICC classification serves as the basis for all clinical studies and is used analogously by all other prostate guideline available [96], [101], [190], [191]. Stages T1-2 N0 M0 are grouped under the term locally-confined prostate carcinoma. Locally-advanced prostate cancer includes stages T3-4 N0 M0. Stages N1and/or M1 are referred to as advanced or metastatic prostate cancer, respectively.

Localized prostate carcinoma is classified into risk groups according to D'Amico et al. (1998) regarding the risk of recurrence [D'Amico, A.V. et al. 1998]:

Low risk: PSA ≤ 10 ng/ml and Gleason score 6 and cT category 1c, 2a.
Intermediate (hereafter: medium) risk: PSA > 10 ng/ml - 20 ng/ml or Gleason score 7 or cT category 2b.
High risk: PSA > 20 ng/ml or Gleason score ≥ 8 or cT category 2c [191], [D'Amico, A.V. et al. 1998]

This risk classification is incorporated into many clinical trials, and the parameters PSA level, Gleason score and T category serve as the basis of nomograms.

Changes in the current UICC classification compared to previous versions should be considered when assessing staging studies. Similarly, changes in the assessment of individual parameters relevant for risk group classification (PSA, Gleason, tumor stage) must be taken into account in the assessment of staging studies and in the selection criteria of therapy recommendations.

5.20 · Evidence-based Recommendation · checked 2018

The DRE findings shall be used to determine the clinical T category. Findings from previously performed imaging procedures shall be considered if they meet the applicable quality standards.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (97%)

5.21 · Evidence-based Recommendation · modified 2018

Patients with tumor category cT1 and low risk parameters should not receive imaging studies for staging (ultrasound, skeletal scintigraphy, CT, PET/CT).

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 2+
to 3 (SIGN)
Consensus: Strong consensus (100%)
References: [193] [194] [195] [196]

Evidence tables (1)

5.3 EvT 5.21

5.22 · Evidence-based Statement · checked 2018

For patients at intermediate risk, no evidence-based recommendations can be made for imaging in the context of staging due to a lack of data.

Level of evidence: 4
Consensus: Strong consensus (100%)

5.23 · Evidence-based Recommendation · checked 2018

Patients with a Gleason score of ≥ 8 or a category cT3/4 should receive an MRI or CT scan of the pelvic organs before deciding on therapeutic intervention, depending on the underlying issue.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 2++
Consensus: Strong consensus (97%)
References: [197]

Evidence tables (1)

5.3 EvT 5.23

5.24 · Evidence-based Recommendation · modified 2018

Patients with histologically-confirmed prostate cancer and a PSA level of > 10 ng/ml or a Gleason score ≥ 8 or a T category cT3/4 or bone pain should receive skeletal scintigraphy.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 2++
Consensus: Majority approval (85%)
References: [197] [198] [199]

Evidence tables (1)

5.3 EvT 5.24

5.25 · Evidence-based Recommendation · new 2021

a. PSMA-PET has a higher accuracy (precision) for detecting prostate cancer metastases than the combination of computed tomography and bone scintigraphy.

(Statement)

b. PSMA-PET/CT can be used in high-risk prostate cancer (Gleason score 8-10 or T category cT3/cT4 or PSA≥20ng/ml) for diagnosis of metastasis.

Recommendation grade: 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
Level of evidence: 1+
Consensus: Strong consensus (a. 100 %, b. 96)
References: [200]

Evidence tables (1)

Hofman_Lancet_2020

5.26 · Consensus-based Recommendation · checked 2018

In case of unclear findings on scintigraphy or suspicion of metastases threatening structural stability, further diagnostic testing in radiology and, if necessary, neurology shall be arranged.

Consensus: Strong consensus (98%)

5.27 · Evidence-based Recommendation · checked 2018

Grade of recommendation: 0

Nomograms can be used to indicate biopsy in cases of suspected prostate cancer and for staging and prognostic assessment in cases of proven prostate cancer.

Grade of recommendation: A

If used, externally validated nomograms shall be used.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 2+
4
Consensus: Consent (95%)
References: [201] [202] [203]

Evidence tables (1)

5.3 EvT 5.27

5.28 · Evidence-based Recommendation · checked 2018

If locally-advanced prostate cancer is suspected and radiotherapy is planned, MRI can be performed to determine the clinical T category if required to accurately define the target volume.

Recommendation grade: 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
Level of evidence: 2++
Consensus: Consent (95%)
References: [204] [205] [206] [207] [208]

5.29 · Evidence-based Recommendation · checked 2018

Level of Recommendation: 0

Level of Evidence: 2+ to 3

In the context of a diagnosis of a recurrence (following primarytreatment with curative intent, see Recommendation 6.2 and 6.3), PET hybrid imaging with radiolabeled PSMA ligands can be performed primarily to assess the extent of tumor disease and to determine whether the findings are of consequence for further treatment.

Grade of Recommendation: A

Level of Evidence: 4

A negative PSMA-PET shall not delay early salvage therapy.

Recommendation grade

A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht

Level of evidence

to 3 (SIGN) (recommendation A)

(Recommendation B)

Consensus

Consent (93%)

References

[209] [210] [211] [212] [213] [214]

Re: Recommendation 5.20

In order to determine the local tumor extension, in addition to the pathomorphological biopsy findings and the DRE, the results of the primary diagnostic imaging already performed (TRUS, MRI, if applicable) should be taken into account if they have been carefully performed and documented according to the quality criteria in place.

Since the test quality parameters of DRE and conventional TRUS are approximately equal with respect to extracapsular extension/infiltration into seminal vesicle [215], [216], and the test quality of the combination of TRUS and DRE is not better than for either procedure (PPV approximately 50%, [217], [218]]), TRUS is not indicated for local staging. The staging used in the literature for "localized" or "locally-advanced" prostate carcinoma is based solely on DRE, without specifying the exact grading criteria. In determining tumor extent, MRI achieves better values than transrectal ultrasound using grayscale techniques [215], [219]. For example, Böni 1996 [215] showed better test quality parameters for MRI (endorectal coil) than for DRE or TRUS [204], [220]. In the first update search (10/2007-12/2010) no comparative studies on newer techniques in transrectal ultrasound versus MRI or functional MRI were identified, therefore no statements can be made on this. No valid newer ultrasound techniques are available for nationwide diagnosis. For the value of MRI or CT and PET/CT for staging, see the following recommendations.

In addition to the assessment of local spread, other findings are essential for treatment planning, estimation of the risk of locally-advanced or metastatic disease (nomograms see below) and estimation of the risk of recurrence (D’Amico classification with PSA value and Gleason score) [D'Amico, A.V. et al. 1998]. The tumor extent on punch biopsy and the number of positive biopsies are needed for assessment of the possibility of an Active Surveillance strategy. See also in the Chapter on pathomorphological examinations.

Re: Recommendations 5.21, 5.22, and 5.23

Meta-analyses from 2001 and 2002 [204], [220] report a sensitivity of 71% and specificity and 74% for MRI for staging. With a specificity of 80%, a sensitivity of 62% to 69% was still achieved. Staging was significantly improved in two retrospective surveys in prostate cancer confirmed by MRI compared with the use of nomograms alone, based on PSA level, Gleason score, and digital-rectal examination [221], [222]. The additional use of MR spectroscopy did not yield a statistically significant advantage over MRI alone. These global evaluations do not account for the benefit of MRI imaging with respect to further treatment decisions. In the following, the studies were analyzed to determine whether conclusions regarding the benefit of MRI imaging for the three different risk groups could be derived. The main purpose of this is to avoid overdiagnosis.

Recommendations on further imaging procedures for staging: for TRUS see Recommendation 5.20, for the value of CT examination see recommendation 5.23. For PET/CT separate recommendations have been formulated under 5.25 and 5.29.

Re: Recommendation 5.21

The following recommendation applies provided that all low-risk criteria according to D’Amico are fulfilled.

For biopsy-proven prostate carcinomas that were preoperatively assessed as "low-risk" tumors, few data are available on the benefit with respect to a change in treatment strategy based on the MRI results. In a retrospective case series in patients with biopsy-proven prostate cancer and low-risk parameters, data are available on the frequency of upstaging (to cT3) and the subsequent change in therapeutic approach ( n total = 144 pat., [193]). Upstaging to cT3 occurred in five patients, and the strategy was changed in two (1.3% of the total group). Other series [223], [224], [225] do not report the proportion of patients with low-risk tumors and do not include information on a change in strategy due to the MRI result.

Furthermore, there are no convincing data for a benefit of MRI in low-risk tumors neither with respect to the certainty of tumor localization [196] or for the distinction between indolent and non-indolent carcinomas in clinically limited carcinomas [194]. MRI is therefore not recommended for staging in low-risk tumors.

Re: Recommendation 5.22

Given that MRI has the best test performance parameters for local staging compared with TRUS-CT-MRI, staging studies were analyzed for results for intermediate-risk tumors.

The existing studies on staging with MRI do not allow specific conclusions to be drawn for patients with intermediate-risk tumors. The studies generally report intermediate PSA values with underlying PSA values that include intermediate risk. However, results for this range are not reported separately. Similarly, no evaluations for a Gleason score of 7 could be identified. T-category classification was generally by cT1 or cT2; differentiation of results for cT2b was not possible. The use of MRI in intermediate-risk tumors for staging is therefore left to the clinical judgment of the treating physicians and should be performed exclusively in the case of a potential change in treatment strategy based on the cross-sectional imaging result (and according to the indications in the following recommendations).

Re: Rcommendation 5.23

For high-risk tumors, MRI imaging is considered reasonable when there is a potential change in treatment strategy, i.e., extraprostatic involvement or seminal vesicle infiltration is detected. CT scan can be considered equivalent to MRI in terms of the question of affected lymph nodes. A weak recommendation was formulated (recommendation grade B), since imaging should not be obligatory but rather should be performed on the basis of individual indication.

The literature shows widely varying values for the test quality parameters for the correct detection of a pT3 category by MRI (1.5 T) (data from six studies: median sensitivity 46.5%, 95% CI 38.5-71.4%; median specificity 88%, 95% CI 73-93.7%). In a group of patients with prostate cancer judged to be high risk, Torricelli et al. 2008 [225] demonstrate a change in treatment strategy in 28.8% of patients who did not undergo surgery due to massive extraprostatic involvement, seminal vesicle infiltration or positive lymph nodes appearing on MRI. A 3-T MRI was used in this study. Another evaluation [226] is available on the diagnostic reliability of the detection of bladder wall infiltration in patients with clinical symptoms. It showed a sensitivity of 78% and a specificity of 87%. In this case, the preoperative diagnosis was confirmed by cystoscopy with biopsy, and the indication for this was also based on clinical symptoms, such that MRI is considered to be an additional examination.

According to a meta-analysis by Abuzallouf et al. (2004) [197], the prevalence of a histologically-confirmed N+ category increases to 22.8% for Gleason > 7 and to 25.7% for T3/4. The diagnostic accuracy of lymph node staging is comparable on MRI and CT. In a study by Wang et al. (2006) [207] involving 411 patients, a positive predictive value of 50% and a negative predictive value of 96% for the presence of lymphogenic metastasis were shown for MRI. This is consistent with the values for CT. Thus, patients with positive MRI or CT findings are very likely to have an N+ category. These patients can thus be spared lymphadenectomy, which may have more side effects, and offered an adequate alternative therapy (see chapter primary hormone ablation therapy and Watchful Waiting). For PET/CT, the review by Krause et al. 2011 [176] reports data from five small studies (25 to 67 patients) with an averaged sensitivity of 61% and specificity of 95% (95% CI not indicated) for staging. The results are subject to uncertainty due to the small numbers of cases in the studies.

Re: Recommendation 5.24

For the evaluation of skeletal whole-body scintigraphy with technetium-labeled phosphonates, the meta-analysis by Abuzallouf 2004 [197] was used as the fundamental basis. A total of 23 studies on bone scintigraphy in patients with newly diagnosed, untreated prostate cancer were analyzed. In particular, the probability of the presence of bone metastases was determined as a function of PSA level, T category, and Gleason score.

The results from the systematic review of the literature [197] ) – mostly retrospective case series – show the following probabilities for the presence of bone metastases depending on the PSA level:

PSA <10 ng/ml: 2.3% (1.7-3.0%)
PSA 10-19.9 ng/ml: 6 % (4.6-7.6 %)
PSA 20-49.9 ng/ml: 15.9 % (12.9-19.2 %)
PSA 50-99.9 ng/ml: 39.2 % (29.0-41.8 %)
PSA >100 ng/ml: 74.9 % (70.8-78.7 %)

Since the prevalence of bone metastases at a PSA level < 10 ng/ml was only 2.3%, bone scintigraphy is not considered to be indicated in this case. It should be noted that there is an increased prevalence of bone metastases with a Gleason Score >7 (see below).

In 2011, there was a debate around defining an indication in relation to a PSA value at 20 ng/ml. The counter-argument was that the presence of bone metastases in approximately 6% of patients with a PSA value of 10-20 ng/ml was too high to tolerate this uncertainty in the context of making decisions on whether to operate. For this reason, the limit value of 10 ng/ml was left unchanged after a further vote.

Staging should be performed in a risk-stratified manner. Accordingly, this still includes:

PSA value > 10 ng/ml
Locally-advanced tumor (T3/4 with a prevalence of bone metastases of 47%);
Gleason score of > 7 (prevalence of bone metastases of 28%);
Bone pain or an unexplained increase or elevation in alkaline phosphatase.

If a risk factor is present, skeletal scintigraphy is recommended as part of primary staging. If SPECT or SPECT-CT (slice imaging) is performed in addition to whole-body bone scintigraphy, the sensitivity and specificity can also be increased [227].

Re: Recommendation 5.25

Imaging diagnostics in the context of local staging and diagnosis of metastasis were not the subject of this update to the S3 guideline. However, due to a recent study on PSMA-PET/CT, the guideline group saw an urgent need to update the previous recommendation on PSMA-PET/CT (5.25; performed only as part of controlled clinical trials). A recent systematic literature search identified one randomized trial and several systematic reviews (see Evidence Tables) that form the basis of the new recommendation.

Hofman et al. 2020 conducted a randomized-controlled trial with a total of 302 patients (ANZCTR12617000005358, proPSMA) who had histologically-confirmed, untreated high-risk prostate cancer ("high-risk", PSA value ≥ 20.0 ng/ml, Gleason score 8-10, clinical stage ≥ T3) and were eligible for curative treatment with radical prostatectomy or radiotherapy [200]. Patients in the intervention group initially received imaging using gallium-68 prostate-specific membrane antigen-assisted positron emission tomography/computed tomography (Ga-68-PSMA-11 PET/CT), and patients in the control group received conventional imaging using CT and bone scan [200]. The primary endpoint was the precision of detection of metastases on initial imaging (as affected pelvic lymph nodes (N) or distant metastases (M)) [200]. The authors reported detected metastases (N or M) in 87 patients (30%) at the first follow-up (within 21 days of randomization) and a precision of detection of 94% (95% confidence interval (CI) 91-98%) in the intervention group versus 75% (95% CI 68-82%) in the control group. Furthermore, there were advantages in terms of sensitivity and specificity for PSMA-PET/CT(Table 4) [200]. PSMA-PET was associated with a high interobserver agreement and fewer equivocal findings than conventional imaging (7% vs. 23%). Further results on secondary endpoints can be found in the accompanying evidence summary.

Table 5: Diagnostic precision in the detection of metastases (primary endpoint).

	First PSMA-PET/CT (intervention group)	First conventional imaging (control group)
True positive	34	18
False positive	2	9
False negative	6	29
True negative	103	94
Sensitivity (95 % CI)	85 % (74 % - 96 %)	38 % (24 %-52 %)
Specificity (95 % CI)	98 % (95 % - 100 %)	91 % (85 %-97 %)
Precision (95 % CI)	94 % (91 %-98 %)	75 % (68 %-82 %)
AUC (95 % CI)	92 % (88 % - 95 %)	65 % (60 %-69 %)
AUC = area under the curve, CI = confidence interval Source: [200]

The results are supported by the evidence summarized in the systematic reviews [228][229]. Overall, a higher accuracy can be ascribed to PSMA-PET/CT compared to conventional imaging, which may influence the intended treatment. One example here is additional therapy may be required in the case of oligometastasis. At this time, it is unclear whether treatment changes resulting from more accurate diagnostics will lead to a prolongation of overall survival or benefits in other endpoints relevant to patients [200]. Data from the phase 2 Oriole trial appear to be promising [230]. Taking into account the data on long-term outcomes, which is not yet robust, and the availability which currently cannot consistently be guaranteed, the guideline group has decided in favor of a "can" recommendation for performing a PSMA-PET/CT for the diagnosis of spread in high-risk prostate cancer. However, a recent evaluation of the randomized proPSMA trial suggests that, at least in the Australian care context, PSMA-PET/CT is cost-effective compared with conventional imaging [200][231]. A review of these data in the German care system and more results on patient-relevant outcomes are needed to reassess the value of PSMA-PET/CT in future guideline updates.

Re: Recommendation 5.26

Despite a lack of scientific evidence, ambiguous skeletal scintigraphic findings should be clarified by MRI or CT. However, for small bones and the long bones conventional radiography is preferred. If the skeletal scintigraphy findings show a fracure risk, the findings are further clarified by CT. This procedure corresponds to good clinical practice.

Re: Recommendation 5.27

The following nomograms are recommended for prediction:

Detection of cancer in a biopsy for suspected prostate carcinoma: nomogram by Chun et al. [203];
Organ-confined tumor growth: nomogram by Steuber et al. [202];
Lymphogenic metastasis: nomogram by Briganti et al. [201];
Prognostic assessment: nomograms by Kattan et al. [232], [233], [234].

Re: Recommendation 5.28

In the case of radiotherapy, the surgical specimen is not available for use as the histological gold standard to aid in treatment. Therefore, noninvasive procedures with the best test quality parameters should be used if the extent of therapy depends on the staging result (determination of tumor extent). Of the diagnostic procedures under consideration, DRE, TRUS, and MRI have the best test quality parameters [204], [205], [206], [207], [208].

Re: Recommendation 5.29

Four papers were identified on the use of PSMA-PET in recurrence diagnosis: one study used systematic histological repeat testing of previously PET-positive lymph nodes and CT as a comparative diagnostic test, three studies compared the PSMA-specific tracer with choline-based PET diagnostics. Compared with CT [235], sensitivity was 18% higher (83% versus 65%) when the PSMA tracer was used in the prospective study (249 lymph nodes), and specificity was reported to be 63%, although it should be noted that no systematic histological repeat testing (performed as template biopsy) was performed and thus no statement can be made with respect to false-negative lymph nodes. In the PET tracer-comparative studies, positive predictive accuracy (PPV) verified by pathohistology was 16% higher (87% versus 71%) with the PSMA-specific tracer in the larger, retrospective study (28 patients after PSMA-PET, 38 patients after fluoroethylcholine-PET [209]). Another retrospective study did not use histopathological follow-up testing but found a significantly higher number of lesions with PSMA ligand compared with choline PET/CT [212]. The prospective study [211] with 38 patients did not perform a systematic histological repeat test, but compared the detection rates of the tracers 18F-fluoromethylcholine and 68Ga-PSMA at different PSA levels and found significantly higher detection rates especially at low PSA levels below 0.5 ng/mL: four times more tracer-positive lesions were found in this subgroup (50% with PSMA versus 12.5% with fluoroethylcholine; at PSA levels >2 ng/mL, detection rates were 86% with PSMA versus 57%). A correlation of positive PSMA-PET results with PSA levels is also evident in the meta-analysis identified [236], which reported 58% positive PSMA-PET scans in biochemical recurrence and PSA levels between 0.2 and 1 ng/mL. However, the result of this meta-analysis cannot be considered very reliable due to limitations of the studies included in it. One of the primary studies [211] also reported that in 63% of patients the treatment plan was changed after PET diagnosis, in 54% this occured solely based on PSMA results. However, no analysis was conducted on whether a demonstrable survival-relevant benefit for the affected patients also followed due to the changed therapeutic approach. Three other studies [210], [213], [214] retrospectively reported the change in treatment planning after PSMA-PET examinations. For example, in some patients, PET-CT led to foregoing radiotherapy and choosing systemic therapy instead. Van Leeuwen et al. analyzed registry data indicating that 68Ga-PSMA-PET led to a change in treatment strategy in 28.6% of patients. In an observational study [214] from a radiotherapy oncology clinic, PSMA-PET-CT results were compared with previously performed conventional imaging. In this study, PET showed positive findings in 46.3% of patients previously classified as tumor-free on conventional imaging. A limitation of these small studies is that the results of PSMA-PET were not systematically verified by histology, and none of the studies tracked and reported patient-relevant outcomes of the respective therapeutic strategies chosen over an appropriate time period. The results presented are from studies of recurrent patients and therefore do not allow for conclusions about the situation in primary disease.

According to Recommendation 7.10, salvage radiotherapy should be started as early as possible (PSA < 0.5 ng/ml). Therefore, the authors advocate recommending salvage therapy immediately in case of negative PSMA-PET, as well as a simultaneous indication for salvage therapy and not waiting until repeated PET imaging is found to be positive.

5.4 Pathomorphological examinations

The following chapter is aligned wih the recommendations of the College of American Pathologists [237], the WHO/UICC [238], the Royal College of Pathologists (RCPath, UK) [239], the International Society of Uropathology (ISUP), the International Collaboration on Cancer Reporting (ICCR, see www.iccr-cancer.org) [240], [241], [242], [243], [244], [245], [246], and the Professional Association of German Pathologists and the German Society of Pathology [247].

It is divided into three parts:

Prognostic factors
General principles for the handling of tissue samples
Special aspects for punch biopsies, specimens from radical prostatectomies (including lymphadenectomies), transurethral resection material (TUR), and enucleated nodular hyperplasia (so-called adenectomy specimen)

5.4.1 Prognostic factors for prostate cancer

5.30 · Evidence-based Recommendation · checked 2018

The following three parameters should be considered for the prognostic evaluation of prostate cancer:

Tumor grading according to Gleason score (according to the current version, see also Recommendation 5.39)
TNM category (according to the TNM classification of the current edition)
Surgical resection margins of the carcinoma

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Consent (95%)
References: [189] [246]

5.31 · Evidence-based Recommendation · checked 2018

To make an estimate of the prognosis, no further investigations (molecular biology, immunohistochemistry, cytometry) shall be performed in routine care beyond pathomorphology.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)

Re: Recommendation 5.30 and 5.31

For determining the prognosis in prostate carcinoma, the Gleason score [248], [249], the TNM category, as well as the R status of the carcinoma have proven to be of key clinical significance [237], [250], [251], [252], [253], [254]. The TNM stage, as well as the R-status, can only be determined jointly by the pathologist and the clinician taking an overview of all the available pathohistological and clinical information. The R-status refers to an indication of the presence of any residual tumor. The pathologist must determine whether the surgical resection margin is tumor-free in relation to R-status. The clinician must report whether distant metastases or clinically apparent residuals are present. Currently, no prospectively relevant markers for prognosis have been identified whereby their significance would justify the use of immunohistochemical, DNA cytometric, or molecular testing [255].

5.4.2 General principles

5.4.2.1 Required clinical information and collection of tissue samples

5.32 · Evidence-based Recommendation · checked 2018

The following information shall be provided to the pathologist: patient data, type of sampling (e.g., punch biopsy, radical prostatectomy, transurethral resection, enucleation), sampling location of tissue specimens, and other relevant clinical information (PSA levels, digital-rectal examination and imaging results, previous conservative treatment)
The prostatectomy specimen shall be sent to the pathologist without prior tissue collection so as not to interfere with tumor-type diagnosis, determination of pT category, and assessment of resection margin
For tissue sampling in the context of scientific investigations, see recommendation 5.50
Fixation shall be performed in an adequate volume of four percent aqueous formaldehyde solution (buffered) (ratio volume: tissue at least 3:1).

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Consent (95%)

Re: Recommendation 5.32

Good cooperation between urologists and pathologists is a prerequisite for optimal pathomorphological diagnosis is. The surgical specimen should be transferred to the fixation solution in the operating room. The prostatectomy specimen should be sent to the pathologist without prior tissue sampling, unless a specific joint agreement has been made in this regard (e.g., for intraoperative frozen section, or similar). A standardized form for preparing reports has proven helpful for documenting the tissue samples taken. Current forms for the documentation of punch biopsies and prostatectomies are currently being revised or developed by the German Society of Pathology and the Professional Association of German Pathologists, respectively. They will be added to this guideline as part of the regular revisions.

5.4.2.2 Histopathological cancer diagnosis and differential diagnosis

5.33 · Evidence-based Recommendation · checked 2018

The following histomorphological criteria are usually required for the diagnosis of acinar adenocarcinoma of the prostate: 1. architectural abnormalities + 2. nuclear atypia + 3. a benign lesion has been ruled out.

If only two of the above criteria are met, the diagnosis of atypical glands or so-called atypical microglandular proliferation (atypical small acinar proliferation – ASAP) or atypical glands suspicious for prostate cancer – ATYP should be made.
Appropriate immunohistochemical staining should be performed to demonstrate the absence of basal cells in unclear cases.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 4
Consensus: Strong consensus (97%)
References: [256] [257] [258] [259] [260] [261] [262]

5.34 · Evidence-based Recommendation · checked 2018

In cases where conventional morphological testing shows clearly benign or malignant lesions, immunohistochemistry shall not be performed.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (97%)

5.35 · Evidence-based Recommendation · checked 2018

In cases where the dignity of a lesion cannot be clearly established by conventional morphological methods, immunohistochemical clarification using one or two basic cell markers shall be performed. In addition, positive markers of prostate cancer can be used.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)

5.36 · Evidence-based Recommendation · checked 2018

Common prostate cancer and its variants shall be subdivided according to the current WHO classification.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)
References: [263]

5.37 · Evidence-based Recommendation · checked 2018

In the presence of prostatic intraepithelial neoplasia (PIN), only "high-grade PIN" shall be mentioned in the histopathologic findings with an additional reference made to a uni-focal or multifocal presentation.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)
References: [108] [110] [112] [258] [264] [265]

5.38 · Evidence-based Recommendation · checked 2018

If there is reasonable doubt about the prostatic origin of a carcinoma, organ-specific markers shall be used to confirm the diagnosis. In addition, markers of tumors considered as part of th differential diagnosis shall be added.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)

Re: Recommendations 5.33 to 5.38

No systematic review on the use of immunohistochemistry was identified in the systematic literature search. In cases presenting with lesions that are clearly benign or malignant on conventional morphology, immunohistochemistry should not be performed. The following immunohistochemical markers are available for the diagnosis of common cancer in cases of doubt:

p63, basal cell keratins: evidence of absence of basal cells around carcinoma glands [259], [260], [261], [262]
p63, CK5/6, CK34ßE12 (immunohistochemical staining with basal cell markers): to show the absence of basal cells in unclear cases and in those cases where conventional morphological methods do not clearly establish the dignity of a lesion
Alpha-methylacyl-CoA racemase (AMACR): used as a "molecular neoplasia marker" for prostate cancer in the diagnosis of difficult cases [266].
PSA, prostein, NKX3.1, ERG, SPP, androgen receptor: evidence of prostate origin [255], [267], [268], [269], [270]
Colon CK20+/CK7-/CDX2+, urothelial CK7(+) and CK20(+), GATA3+, p63+: markers for tumors considered for differential diagnosis

Common prostate carcinoma refers to epithelial adenocarcinoma, which accounts for the vast majority of prostate carcinomas. The current 2016 WHO classification continues to list rare prostate cancers, and those without a particular differention (e.g., prostate cancer with numerous endocrine cells, pseudohyperplastic, atrophic, xanthomatous, mucinous, ductal, signet-ring cell, and sarcomatoid carcinoma, basal cell carcinoma, urothelial carcinoma, squamous cell carcinoma, well-differentiated neuroendocrine tumor = carcinoid, poorly differentiated neuroendocrine carcinoma = small cell carcinoma), and benign and atypical lesions, which must be differentiated from prostate cancer (prostatic intraepithelial neoplasia – "PIN", adenomatous, cribriform, postatrophic hyperplasia, sclerosing adenosis, nephrogenic adenoma, verumontanum gland hyperplasia, seminal vesicle epithelium, Cowper glands, etc.).
Other recommended immunohistochemical markers for diagnosis and differential diagnosis of these lesions are chromogranin, synaptophysin, S100, and actin.

In patients diagnosed with ASAP, the rate of invasive cancer on follow-up biopsy testing is reported to be 42-48% [108], [109]. Therefore, rebiopsy should be performed in this case. The so-called PIN lesion (prostatic intraepithelial neoplasia) is divided into a "low-grade"- and a "high-grade"-PIN lesion [271], [272]. Only the "high-grade"-PIN lesion (HGPIN) is considered a facultative precursor lesion and (especially when multifocal in punch biopsies) an indicator lesion of peripheral zone cancer [112], [258], [264], [265]. However, a systematic review including recent literature does not show a significantly higher rate of invasive carcinoma in follow-up biopsies compared having patients with rebiopsy after a benign diagnosis. A median of 24.1% of cases were diagnosed with invasive cancer [111]. The reduction in invasive carcinoma at rebiopsy in recent times has been attributed to the higher number of tissue samples collected at initial biopsy. However, in the case of extensive high-grade PIN (detection in at least four tissue samples), the risk increases to 39% (data from a retrospective case series), such that in this case rebiopsy is also recommended in this case [112].

For ASAP and high-grade PIN, see also chapter 5.1 in the section on punch biopsy of the prostate.

5.4.2.3 Grading

5.39 · Evidence-based Recommendation · modified 2018

When reporting the tumor grade, the Gleason score shall be reported according to ISUP 2014 / WHO 2016.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)
References: [189] [246]

5.40 · Evidence-based Recommendation · checked 2018

In addition to the subclassification of pT2 carcinoma, a metric measurement of the tumor size shall be reported.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (98%)

Re: Recommendations 5.39 and 5.40

For the grading of ordinary prostate carcinoma, the Gleason grading system (Gleason score) according to the ISUP consensus conference of 2005 has become accepted worldwide and is now being applied according to a revised version [246].

The Gleason score should not be determined for: conservatively pretreated ordinary cancer, adenosquamous and squamous cell carcinoma, urothelial carcinoma, basal cell carcinoma, small cell carcinoma.

Under the current TNM classification, subcategories are no longer defined for the pT2 category [189]. Also, the prognostic value of tumor volume in pT2 tumors has not yet been conclusively clarified [273]. Until such a time, it is recommended to provide a metric measurement of the tumor size (e.g., tumor volume, maximum diameter of the index tumor, ratio of positive blocks (related to total number of blocks of transverse slices), tumor invasion in percent) [274], [275].

5.4.3 Special aspects for taking different tissue specimens

5.4.3.1 Punch biopsy

5.41 · Evidence-based Recommendation · checked 2018

Each tissue sample shall be clearly attributable to a localization.
The pathologist shall determine the number and length of the tissue samples. The punch cylinders shall be embedded as flat and in their entire length and processed in layered sections (at least five layered sections steps per paraffin block).

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)
References: [276] [277]

5.42 · Evidence-based Recommendation · checked 2018

In case of positive detection of a carcinoma, the following information shall be provided by the pathologist to the urologist:

Number and location of carcinoma-positive tissue samples
Semiquantitative estimate of tumor extent (in percent and/or mm)
Gleason score according to ISUP 2014 and WHO 2016
If assessable, perineural sheath infiltration (Pn1), capsular infiltration, cross-capsular growth, and seminal vesicle infiltration shall be reported

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Consent (95%)
References: [278] [279] [280] [281] [282]

Evidence tables (1)

5.4.3.1 EvT 5.42

5.43 · Evidence-based Recommendation · checked 2018

In the absence of carcinoma being detected, information on the representativeness of the specimens and on PSA-relevant findings (e.g., nonspecific or so-called granulomatous prostatitis, nodular hyperplasia, infarction).shall be provided.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)

5.44 · Evidence-based Recommendation · checked 2018

After hormone-ablation therapy (LH-RH analogs, antiandrogens) or radiotherapy, semiquantitative regression grading (low, moderate, high) can be performed.

Recommendation grade: 0: offene Empfehlung (Option) bzgl. einer Maßnahme - verwendete Ausdrucksweise = kann
Level of evidence: 4
Consensus: Strong consensus (100%)
References: [283]

Evidence tables (1)

5.4.3.1 EvT 5.44

Re: Recommendation 5.41

Punch biopsies shall be taken according to the chapter on punch biopsy of the prostate (usually ten to twelve tissue cylinders, five to six cylinders each from the right and left prostate lobes – apex, middle, base lateral, and medial respectively). If necessary, additional biopsies should be taken from clinically suspicious areas. All specimens shall be localized by appropriate indications [278], (see chapter 5.1 on Punch biopsy of the prostate). Needle size should be 20 gauge if possible.

Prostate punch biopsies can be placed on foam plates (or filter paper) for stretched fixation (in four percent aqueous formaldehyde solution (buffered)), for example.

In case of an unclear biopsy result: see chapter 5.1 on punch biopsy of the prostate.

Re: Recommendations 5.42 – 5.44

In order to ensure clarity, it is recommended that uniform frameworks be used for pathological documentation and comparisons. (For example, the forms provided by the German pathology guidelines on prostate cancer are recommended for this purpose (S1 guideline on prostate cancer: https://www.pathologie.de/?eID=downloadtool&uid=1698). At the same time, this serves as a measure for quality assurance and therefore means incorrect treatment can be avoided. The regulated vocabulary used for prostate cancer (https://art-decor.org/art-decor/decor-datasets--pathdv-?id=&effectiveDate=&conceptId=&conceptEffectiveDate) set out by the German Association of Pathologists for use in clinical and pathological documentation frameworks includes the documentation contents listed in chapter 5.4.

The information required in cases of positive detection of carcinoma includes tumor extent in each individual punch biopsy, either as a percentage or by reporting absolute length (mm). Signs of prostate cancer regression after hormone-ablation therapy or radiotherapy include cytoplasmic vacuolization and nuclear pyknosis [284], [285], [286].

Immunohistochemical PSA staining is useful for identifying tumor cells showing regressive changes. A proposal for quantification of tumor regression as low, moderate, and high has been developed by Dhom and Degro [283]. However, there is no international standard for grading the regression of treated prostate carcinomas.

5.4.3.2 Specimens from radical prostatectomy

5.45 · Evidence-based Recommendation · checked 2018

The following procedure shall be followed for macroscopic processing:

Prostatectomy specimens shall be measured in three dimensions (mm).
To determine the minimum margin, the specimen shall be marked ventrally and dorsally in different colors with india ink.
Vesical and apical margin areas shall also be marked with india ink. Both surfaces should be separated in the form of 3-5 mm thick slices at right angles to the urethra.
The slices shall then be prepared as slices parasagittally and completely embedded.
The resection margins of both of the vas deferens and both seminal vesicles shall be embedded in a laterally separated manner.
The prostatectomy specimen shall be prepared as slices in the transverse plane as 3-5 mm thick slices, and embedded as completely as possible (large-area sections or oriented in normal histology capsules).

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (97%)

5.46 · Evidence-based Recommendation · checked 2018

The microscopic evaluation shall include the following information:

Indication of the location of the carcinoma with a semiquantitative estimation of the tumor extent ( % of affected parenchyma).
Indication of the pT category as well as other parameters concerning the prostate cancer (as well as for the punch biopsy).
Due to its prognostic significance, subdivision of the category pT3a (extracapsular spread = tumor in fatty tissue) according to Epstein et al. [250] into focal capsular penetration (few tumor glands immediately outside the prostate in one to two sections) and established capsular penetration (= higher extent of penetration).
Indication of surgical resection margin. If the margin is clear, the minimum margin distance shall be given in mm.
In case of R1 status (= positive for residual tumor) due to a non-tumor-free margin, the location of the margin showing involvement by the carcinoma (posterior, postero-lateral, anterior, apical, proximal-vesical, distal-urethral), the extent of involvement (in mm), and the absence or presence of the prostate capsule in this area shall be indicated.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (96%)

Re: Recommendations 5.45 and 5.46

The anatomical basis for descriptions and assessments of the prostate is the anatomical prostate model according to McNeal [287], [288] with the prostate divided up according to its embryogenesis and the histogenesis of the carcinoma into three zones: the central zone (10% of prostate cancers), the transitional zone (15 to 20% of prostate cancers, mostly so-termed the incidental carcinomas) and the peripheral or posterolateral zone (70 to 75% of prostate carcinomas, manifest carcinomas).

Anatomical features of the prostate:

The so-called "capsule" is merely a region of poorly-defined fibromuscular stroma. Diagnosis of pT3a only in case of definite extracapsular invasion (tumor in fatty tissue);
In the area of apex, neuromuscular bundle, bladder outlet and anteriorly, there is no capsule. In the apex area and anteriorly presence of striated muscle. Diagnosis of extraprostatic spread is difficult or even impossible to determine in these locations. Diagnosis of bladder neck infiltration (pT4) only if there is infiltration of typical bladder detrusor musculature (muscularis propria);
Due to the prognostic significance of the R-status [237], [250] and the frequent occurrence of multifocal prostate cancers [289], [290], [291] radical prostatectomy specimens should be completely embedded [292]. Whether the minimum margin distance should be stated in mm has been discussed with much controversy arising by the group of authors, since this feature is not regularly of therapeutic consequence. However, a standardized workup was welcomed; therefore, the recommendation was retained. In contrast, selection can be carried out for high-grade BPH (>50g).
A tumor-free margin is not synonymous with R-status, as this refers to the presence of residual tumor of any location (e.g., including distant metastasis). Accordingly, microscopic tumor involvement of the settling margin should be assumed to be R1 status, and macroscopic tumor involvement should be assumed to be R2 status.
The prognostic relevance of the tumor volume is not certain [293] and an exact determination of this as part of routine diagnostic testing is very difficult to achieve. Therefore, the determination of tumor volume is not recommended;
Optionally, intraoperative frozen section in case of planned nerve-sparing radical prostatectomy [294], [295].

5.4.3.3 Transurethral resection material ("Turp") and enucleated nodular hyperplasia (also known as 'adenectomy specimens')

5.47 · Evidence-based Recommendation · checked 2018

The material should be weighed. At least ten capsules should be embedded. Of the remaining material, one additional capsule should be embedded for each 3 g.

Recommendation grade: B: Empfehlung für oder gegen eine Maßnahme - verwendete Ausdrucksweise = sollte/sollte nicht
Level of evidence: 4
Consensus: Strong consensus (100%)
References: [296] [297]

5.48 · Evidence-based Recommendation · checked 2018

If an incidental carcinoma, a suspicious tumor, or a potentially precancerous change (e.g. atypical adenomatous hyperplasia, "High-Grade-PIN") is detected, the residual material shall be completely embedded if this has therapeutic consequences.

If an incidental carcinoma is detected, Gleason grading shall be performed, the T category (T1a, T1b) shall be determined, and other parameters related to the prostate cancer shall be specified (see the section on tissue samples from punch biopsy).

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (97%)
References: [298]

Re: Recommendations 5.47 and 5.48

Incidental prostate carcinoma is found in 8.6% to 15% of samples submitted from transurethral resection or enucleated nodular hyperplasia [296], [298], [299]. In this regard, the frequency of incidental carcinoma detected depends on how complete the of the workup of the material is [296], [297]. However, a uniform recommendation on how extensive the processing should be does not yet exist. A complete workup of the residual material is recommended in light of the clinical consequences of a possible tumor diagnosis. In this regard, age, comorbidity, and the patient's wishes play a role. To ensure a correct T-category is determined, a complete workup of the material is required if an incidental carcinoma is detected [298].

5.4.3.4 Regional lymphadenectomy

5.49 · Evidence-based Recommendation · checked 2018

All lymph nodes shall be macroscopically dissected and then embedded, examined, and counted to determine the lymph node category. The lymph nodes shall be assessed separately according to the regions indicated. After histological examination, the pN category (pN0 or pN1) shall be determined. The total number and the number of affected lymph nodes shall be indicated, as well as the diameter of the largest metastasis.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (97%)

Re: Recommendation 5.49

Lymphadenectomy plays an essential role in determining the extent of the tumor (see chapter 6.4.4 on lymphadenectomy). Accordingly, all macroscopically dissectible lymph nodes must be completely embedded and examined [300]. To be able to assess separately by region, the lymph nodes shall be sent to the pathologist separately according to the region. Some parameters relating to lymphogenic metastasis (micro/macro infestation, extracapsular growth) require further clarification with regard to their prognostic significance. For example, there has not been any conclusive clarification with regards to the prognostic value of extracapsular tumor growth, which is considered to be important, especially by radiotherapists. On the other hand, there is evidence that metastasis size may be more prognostically significant than the mere number of nodal metastases [241], [301], [302].

5.4.4 Scientific studies on tissue samples

5.50 · Evidence-based Recommendation · checked 2018

Tissue sampling for scientific or other investigations shall only be performed with the informed consent of the patient and an approval on ethics voting.
Tissue samples shall be taken by the urologist or the pathologist with mutual collaboration and agreement between the parties. The collection and localization of the tissue samples shall be documented on the submission form.
A conventionally stained (HE) section of all preserved specimens shall be evaluated as part of diagnostic testing as a control.

Recommendation grade: A: Starke Empfehlung für oder gegen ein Maßnahme - verwendete Ausdrucksweise = soll/soll nicht
Level of evidence: 4
Consensus: Strong consensus (100%)
References: [303] [304]

Re: Recommendation 5.50

Since classification, grading, correct TNM classification, as well as the R-status of the tumor all represent vital prognostic information, the pathologist shall be directly involved in tissue collection for scientific investigations. For the same reasons, a pathohistological, diagnostic evaluation of the preserved tissue (in the form of frozen sections or conventional sections) is required.

Evidence tables

5.1 EvT 5.2

Quelle	Fazit/Empfehlung	Empfehlungsgrad	Evidenzgraduierung	Literaturbelege
EAU 2007	Ultrasound-guided transrectal 18G core biopsy has become the standard way to obtain material for histopathological examination. Multiple cores can be taken with a low risk of complications if antibiotic prophylaxis is used. Lesion-guided biopsies can be used in cases where there is a palpable nodule in combination with a high PSA-level. Recently, the standard way of obtaining sextant biopsies has been replaced by laterally directed sextant biopsies in order to optimize the CaP detection rate (35,36). Biopsy cores obtained this way include biopsies from the posterolateral aspect of the peripheral zone, which is the most common location for early CaP. The number of biopsies required for the optimal detection of CaP is controversial. If the first set of biopsies is negative, repeated biopsies can be recommended. In cases where high-grade prostatic intraepithelial neoplasia (HGPIN) or atypical small acinar proliferation (ASAP) is present, as many as 50-100% of prostates harbour a concomitant cancer and re-biopsy is indicated. With an increasing number of men undergoing more extensive biopsies on possibly two or even more occasions, the need for analgesia has become more important in clinical practice. Of various methods examined, the use of a periprostatic injection with a local anaesthetic seems to combine best high-efficacy with easy application and low complication rates. Of 23 studies, 20 showed good efficacy when compared to placebo or intrarectal gel with local anaesthetic (level of evidence: 1a).	-	- 1a	31,32 - 35,36 43,44 49-71
National Comprehensive Cancer Network 2007	Initial and Repeat; Extended pattern biopsy (12 cores) Number of Cores: · Sextant (6) and · Lateral peripheral zone (6) and · Lesion-directed at palpable nodule or suspicious image. Transition zone biopsy is not supported in routine biopsy. However, the addition of a transition zone biopsy to an extended biopsy protocol may be considered in a repeat biopsy if PSA is persistently elevated. After 2 negative extended TRUS biopsies, prostate cancer is not commonly found at repeat biopsy. For high risk men with multiple negative biopsies, consideration can be given to a saturation biopsy strategy. Local anesthesia can decrease pain/discomfort associated with prostate biopsy. Follow-up for TRUS Biopsies: Cancer -> treatment Atypia suspicious for cancer -> extended pattern rebiopsy (within 3 mo) with increased sampling of ASAP site and adjacent areas. If no cancer found, close Follow-up with PSA and DRE. High-grade PIN -> if initial sextant biopsy used, rebiopsy using extended pattern, if extended pattern used initially, immediate repeat biopsy is probably not necessary within the first year. Benign: Follow-up, based on DRE and PSA findings.	2A	--	--
NICE 2008	Imaging is not routinely recommended for men in whom no radical treatment is intended. Computerised tomography (CT) of the pelvis is not recommended for men with low- or intermediate- risk localised prostate cancer (see table A). Men with high-risk localised (see table A) and locally advanced prostate cancer who are being considered for radical treatment should have pelvic imaging with either magnetic resonance imaging (MRI), or CT if MRI is contraindicated. Magnetic resonance spectroscopy is not recommended for men with prostate cancer except in the context of a clinical trial. Isotope bone scans are not routinely recommended for men with low-risk localised prostate cancer. Isotope bone scans should be performed when hormonal therapy is being deferred through watchful waiting in asymptomatic men who are at high risk of developing bone complications. Positron emission tomography imaging for prostate cancer is not recommended in routine clinical practice.

5.1 EvT 5.3

Quelle	Fazit/Empfehlung	Empfehlungs- grad	Evidenz-graduierung	Literatur- belege
National Comprehensive Cancer Network 2007	Initial and Repeat; Extended pattern biopsy (12 cores) Number of Cores: · Sextant (6) and · Lateral peripheral zone (6) and · Lesion-directed at palpable nodule or suspicious image. Transition zone biopsy is not supported in routine biopsy. However, the addition of a transition zone biopsy to an extended biopsy protocol may be considered in a repeat biopsy if PSA is persistently elevated. After 2 negative extended TRUS biopsies, prostate cancer is not commonly found at repeat biopsy. For high risk men with multiple negative biopsies, consideration can be given to a saturation biopsy strategy. Local anesthesia can decrease pain/discomfort associated with prostate biopsy. Follow-up for TRUS Biopsies: Cancer -> treatment Atypia suspicious for cancer -> extended pattern rebiopsy (within 3 mo) with increased sampling of ASAP site and adjacent areas. If no cancer found, close Follow-up with PSA and DRE. High-grade PIN -> if initial sextant biopsy used, rebiopsy using extended pattern, if extended pattern used initially, immediate repeat biopsy is probably not necessary within the first year. Benign: Follow-up, based on DRE and PSA findings.	2A	--	--
NICE 2008	Imaging is not routinely recommended for men in whom no radical treatment is intended. Computerised tomography (CT) of the pelvis is not recommended for men with low- or intermediate- risk localised prostate cancer (see table A). Men with high-risk localised (see table A) and locally advanced prostate cancer who are being considered for radical treatment should have pelvic imaging with either magnetic resonance imaging (MRI), or CT if MRI is contraindicated. Magnetic resonance spectroscopy is not recommended for men with prostate cancer except in the context of a clinical trial. Isotope bone scans are not routinely recommended for men with low-risk localised prostate cancer. Isotope bone scans should be performed when hormonal therapy is being deferred through watchful waiting in asymptomatic men who are at high risk of developing bone complications. Positron emission tomography imaging for prostate cancer is not recommended in routine clinical practice.

Quelle

Fazit/Empfehlung

Empfehlungs- grad

Evidenz-graduierung

Literatur-
belege

National Comprehensive Cancer Network 2007

Initial and Repeat; Extended pattern biopsy (12 cores)

Number of Cores:

· Sextant (6) and

· Lateral peripheral zone (6) and

· Lesion-directed at palpable nodule or suspicious image.

Transition zone biopsy is not supported in routine biopsy. However, the addition of a transition zone biopsy to an extended biopsy protocol may be considered in a repeat biopsy if PSA is persistently elevated.

After 2 negative extended TRUS biopsies, prostate cancer is not commonly found at repeat biopsy.

For high risk men with multiple negative biopsies, consideration can be given to a saturation biopsy strategy.

Local anesthesia can decrease pain/discomfort associated with prostate biopsy.

Follow-up for TRUS Biopsies:

Cancer -> treatment

Atypia suspicious for cancer -> extended pattern rebiopsy (within 3 mo) with increased sampling of ASAP site and adjacent areas. If no cancer found, close Follow-up with PSA and DRE.

High-grade PIN -> if initial sextant biopsy used, rebiopsy using extended pattern, if extended pattern used initially, immediate repeat biopsy is probably not necessary within the first year.

Benign: Follow-up, based on DRE and PSA findings.

NICE 2008

Imaging is not routinely recommended for men in whom no radical treatment is intended.

Computerised tomography (CT) of the pelvis is not recommended for men with low- or intermediate- risk localised prostate cancer (see table A).

Men with high-risk localised (see table A) and locally advanced prostate cancer who are being considered for radical treatment should have pelvic imaging with either magnetic resonance imaging (MRI), or CT if MRI is contraindicated.

Magnetic resonance spectroscopy is not recommended for men with prostate cancer except in the context of a clinical trial.

Isotope bone scans are not routinely recommended for men with low-risk localised prostate cancer.

Isotope bone scans should be performed when hormonal therapy is being deferred through watchful waiting in asymptomatic men who are at high risk of developing bone complications.

Positron emission tomography imaging for prostate cancer is not recommended in routine clinical practice.

Studientyp	Autoren, Jahr	untersuchte Studien/ Materialien	Welche Interventionen wurden geprüft	Ergebnisse	Bemerkungen	Level of Evidence	Literaturbelege
System. Review/Metaanalyse	Eichler 2006	87 Studien (7 RCTs) mit 20.698 Patienten aus systematischer Suche in Medline, Premedline, Cochrane Library, Embase, Biosis, Pascal, Lilacs u.a. bis Mai 2004.	PCa-Nachweis (Cancer Yield) bei erweiterten Biopsie-Protokollen im Vergleich zu Standard-Biopsie (systematic sextant biopsy protocol) = insg. 6 Zylinder bilateral aus MPZ* (=Zonen 2+4).	18-22 Zylinder aus Zonen 1-5* (LPZ+MPZ+TZ+MLiPZ) ergeben 48% mehr PCa-Nachweise (signifikant). 12 Zylinder aus Zonen 1 und 5, 2 und 4 (MPZ+LPZ) ergeben 31% mehr PCa-Nachweise (signifikant). 10 Zylinder aus Zonen 1 und 5, 2 und 4 (MPZ+LPZ) ergeben 25%% mehr PCa-Nachweise (signifikant). Die zusätzliche Entnahme von Zylindern aus TZ zu bereits durchgeführten MPZ+LPZ-Zylindern erbringt keinen signifikanten Mehr-Nachweis. In multivarianter Analyse ergab sich kein signifikanter Unterschied in PCa-Nachweis zwischen 18-22 Zylindern aus Zonen 1-5 oder 12 Zylindern aus MPZ+LPZ oder 10 Zylindern aus Zonen 1-5. Spärliche Ergebnisse zu Nebenwirkungen, aber keine signifikanten Unterschiede zwischen verschiedenen Verfahren; schwere Komplikationen selten: Infektionen in 0-1,8%, schwere Blutungen 0-0,6%, keine Todesfälle.	Autoren empfehlen zur Erlangung eines höheren PCa-Nachweises entweder 12 Zylinder in MPZ+LPZ oder 10 Zylinder in MPZ+LPZ. Es wird jedoch auch die klinische Signifikanz eines höheren Nachweises und die Gefahr von Überdiagnose diskutiert.	1++	18, 43-45, 52-60, 63,67, 70-76, 85-91

Studientyp

Autoren, Jahr

untersuchte Studien/
Materialien

Welche Interventionen wurden geprüft

Ergebnisse

Bemerkungen

Level of Evidence

Literaturbelege

System. Review/Metaanalyse

Eichler 2006

87 Studien (7 RCTs) mit 20.698 Patienten aus systematischer Suche in Medline, Premedline, Cochrane Library, Embase, Biosis, Pascal, Lilacs u.a. bis Mai 2004.

PCa-Nachweis (Cancer Yield) bei erweiterten Biopsie-Protokollen im Vergleich zu Standard-Biopsie (systematic sextant biopsy protocol) = insg. 6 Zylinder bilateral aus MPZ* (=Zonen 2+4).

18-22 Zylinder aus Zonen 1-5* (LPZ+MPZ+TZ+MLiPZ) ergeben 48% mehr PCa-Nachweise (signifikant).

12 Zylinder aus Zonen 1 und 5, 2 und 4 (MPZ+LPZ) ergeben 31% mehr PCa-Nachweise (signifikant).

10 Zylinder aus Zonen 1 und 5, 2 und 4 (MPZ+LPZ) ergeben 25%% mehr PCa-Nachweise (signifikant).

Die zusätzliche Entnahme von Zylindern aus TZ zu bereits durchgeführten MPZ+LPZ-Zylindern erbringt keinen signifikanten Mehr-Nachweis.

In multivarianter Analyse ergab sich kein signifikanter Unterschied in PCa-Nachweis zwischen 18-22 Zylindern aus Zonen 1-5 oder 12 Zylindern aus MPZ+LPZ oder 10 Zylindern aus Zonen 1-5.

Spärliche Ergebnisse zu Nebenwirkungen, aber keine signifikanten Unterschiede zwischen verschiedenen Verfahren; schwere Komplikationen selten: Infektionen in 0-1,8%, schwere Blutungen 0-0,6%, keine Todesfälle.

Autoren empfehlen zur Erlangung eines höheren PCa-Nachweises entweder 12 Zylinder in MPZ+LPZ oder 10 Zylinder in MPZ+LPZ.

Es wird jedoch auch die klinische Signifikanz eines höheren Nachweises und die Gefahr von Überdiagnose diskutiert.

1++

18, 43-45, 52-60, 63,67, 70-76, 85-91

5.1 EvT 5.4

Studientyp	Autoren, Jahr	untersuchte Studien/ Materialien	Welche Interventionen wurden geprüft	Ergebnisse	Bemerkungen	Level of Evidence	Literaturbelege
System. Review	Bootsma 2008	6 RCTs aus systematischer Suche in Medline, Embase, Cochrane bis 2006 oder März 2007.	Antibiotika-Prophylaxe vor Biopsie vs. keine Prophylaxe bezüglich verschiedener Out-comes: Bakteriurie, Bakteriämie, Fieber, Harnwegsinfekt.	Bakteriurie: 4 Studien mit signifikant weniger in Antibiotika-Gruppe, 2 Studien ohne signifikante Unterschiede. Bakteriämie: kein signifikanter Unterschied (4 RCTs). Fieber: kein signifikanter Unterschied in 4 RCTs, signifikanter Unterschied in 1 kleinem RCT. HWI: kein signifikanter Unterschied in 1 RCT (457 Pat.), signifikanter Unterschied in 1 anderen RCT (231 Pat.).	Suchzeitraum nicht klar festgelegt, keine Metaanalyse, Evidenztabellen z.T. missverständlich (Signifikanz).	1+ - 1(-)	27-32

Studientyp

Autoren, Jahr

untersuchte Studien/
Materialien

Welche Interventionen wurden geprüft

Ergebnisse

Bemerkungen

Level of Evidence

Literaturbelege

System. Review

Bootsma 2008

6 RCTs aus systematischer Suche in Medline, Embase, Cochrane bis 2006 oder März 2007.

Antibiotika-Prophylaxe vor Biopsie vs. keine Prophylaxe bezüglich verschiedener Out-comes: Bakteriurie, Bakteriämie, Fieber, Harnwegsinfekt.

Bakteriurie: 4 Studien mit signifikant weniger in Antibiotika-Gruppe, 2 Studien ohne signifikante Unterschiede.

Bakteriämie: kein signifikanter Unterschied (4 RCTs).

Fieber: kein signifikanter Unterschied in 4 RCTs, signifikanter Unterschied in 1 kleinem RCT.

HWI: kein signifikanter Unterschied in 1 RCT (457 Pat.), signifikanter Unterschied in 1 anderen RCT (231 Pat.).

Suchzeitraum nicht klar festgelegt, keine Metaanalyse, Evidenztabellen z.T. missverständlich (Signifikanz).

1+ - 1(-)

27-32

5.1 EvT 5.5

Studientyp	Autoren, Jahr	untersuchte Studien/ Materialien	Welche Interventionen wurden geprüft	Ergebnisse	Bemerkungen	Level of Evidence	Literaturbelege
System. Review/Metaanalyse	Hergan 2007	14 RCTs aus systematischer Suche in Medline, Cochrane, Embase, Handsuche und AUA-Abstracts bis Oktober 2005).	Infiltrative periprostatische Lokal-anästhesie vs keine Lokalanästhesie; Studien zu lokalen Gels oder systemischer Analgesie/Anästhesie wurden ausgeschlossen.	Durchschnittliche Differenz in Schmerz-Scores (VAS 0-10) von -1,05 (95%CI -1,40 bis -0,71 = signifikant) mit Lokalanästhesie vs ohne.	Methodisch einwandfreie Arbeit.	1++	7,8,10, 12-22
System. Review/Metaanalyse	Richman 2006	16 RCTs aus systematischer Suche in Pubmed bis August 2005.	Periprostatischer Block vs. keine Lokalanästhesie.	Durchschnittliche Differenz in Schmerz-Scores (VAS) in allen Studien von -1,66 (95%CI -2,03 bis -1,29 = signifikant) mit Lokalanästhesie vs ohne. Durchschnittliche Differenz in Schmerz-Scores (VAS) nur in verblindeten Studien von -1,36 (95%CI -1,90 bis -0,82 = signifikant) mit Lokalanästhesie vs ohne.	11 Studien wurden auch in Review von Hergan et al. verwendet.	1++	5-20
System. Review/ Metaanalyse	Tiong 2007	25 RCTs aus systematischer Suche in Medline, Cochrane, Embase bis August 2005.	Periprostatischer Block vs keine Anästhesie, verschiedene Techniken und Dosierungen bei periprostatischem Block untereinander, Schmerzreduktion in Abhängigkeit von Zahl der Biopsien, topische Anästhesie vs periprostatischer Block, topische Anästhesie vs keine Anästhesie.	Durchschnittliche Differenzen in Schmerz Scores (VAS) für die verschiedenen Vergleichsgruppen: Block vs keine Anästhesie (20 Studien): -2,09 (95%CI -2,44 bis -1,75 = signifikant). Verschiedene Techniken (20) und Dosierungen (20) für Block: mit Ausnahme der Injektionstechnik lateral der Prostata oder Samenbläschen kein signifikanter Unterschied in Schmerzreduktion zwischen den verschiedenen Techniken. Scherzreduktion und Zahl der Biopsien (20 Studien) kein signifikanter Unterschied. Topische Anästhesie vs Block (6 Studien): signifikant stärkere Schmerzreduktion durch Block (-1,53). Topische Anästhesie vs keine Anästhesie (5 Studien): keine signifikante Differenz in Schmerzreduktion: -0,22 (95%CI -0,56 bis 0,12).	Noch umfangreichere Arbeit als Richman und Hergan.	1++	14, 19, 34-56

5.2 EvT 5.8

Studientyp	Autoren, Jahr	untersuchte Studien / Materialien	Welche diagnostischen Interventionen wurden geprüft?	Welcher Referenzstandard wurde herangezogen?	Ergebnisse (Testgüte-Parameter)	Bemerkungen	Level of Evidence	Literaturbelege
Metaanalyse	Hoogendam, 1999	14 Studien aus systematischer Suche 1983 bis 1995, unselektierte Patienten mit Vd.a. PCA auf Grund von verdächtigem PSA oder TRUS	DRE	Histologie aus Biopsie oder chirurg. Präparat	Gepoolte Ergebnisse aller 14 Studien: Sensitivität 59% (51-67%) Spezifität 94% (91-96%) PPW* 28% (20-36%) NPW** 99% (98%-99%) Gepoolte Ergebnisse der 5 qualitativ besten Studien: Sensitivität 64% (47-80%) Spezifität 97% (95-99%) PPW* 47% (29-64%) NPW** 99% (98-99%)	Nicht alle Studien definieren, was „positive DRE“ bedeutet, unterschiedlich bewertete Studienqualität, Histologien von Biopsien und chirurg. Präparaten sind nur begrenzt vergleichbar	2++	10-14, 16, 18, 19, 21, 23, 25, 26, 29, 30

Studientyp

Autoren, Jahr

untersuchte Studien / Materialien

Welche diagnostischen Interventionen wurden geprüft?

Welcher Referenzstandard wurde herangezogen?

Ergebnisse

(Testgüte-Parameter)

Bemerkungen

Level of Evidence

Literaturbelege

Metaanalyse

Hoogendam,
1999

14 Studien aus systematischer Suche 1983 bis 1995, unselektierte Patienten mit Vd.a. PCA auf Grund von verdächtigem PSA oder TRUS

DRE

Histologie aus Biopsie oder chirurg. Präparat

Gepoolte Ergebnisse aller 14 Studien:

Sensitivität 59% (51-67%)

Spezifität 94% (91-96%)

PPW* 28% (20-36%)

NPW** 99% (98%-99%)

Gepoolte Ergebnisse der 5 qualitativ besten Studien:

Sensitivität 64% (47-80%)

Spezifität 97% (95-99%)

PPW* 47% (29-64%)

NPW** 99% (98-99%)

Nicht alle Studien definieren, was „positive DRE“ bedeutet, unterschiedlich bewertete Studienqualität, Histologien von Biopsien und chirurg. Präparaten sind nur begrenzt vergleichbar

2++

10-14, 16, 18, 19, 21, 23, 25, 26, 29, 30

Artikel (Autor, Jahr, Journal)	Studientyp, prospektiv/ retrospektiv	Anzahl der Patienten	Patientenmerkmale	Diagnost. Intervention	Referenz-Standard	Ergebnisse (Testgüte-Parameter)	Bemerkungen	Evidenz-Niveau (SIGN)
Philip, 2005	Prospektive Kohorte, konsekutiver Patienteneinschluss	408	Vorstellig zur Diagnostik bei erhöhtem PSA (2,5-10 ng/ml)	DRE	Histologie aus Biopsie (408 Patienten) oder aus Prostatektomie-Präparat (82 Patienten)	Prävalenz: 152 bioptisch bestätigte PCAs von 408 Patienten (37%) Testgüte-Parameter für Primärdiagnose PCA: Sensitivität 61% Spezifität 60% PPW* 47% NPW** 72% „keine signifikante Korrelation zwischen DRE- und Biopsie-Stadium“ „sehr schlechte Übereinstimmung zwischen DRE und pathologischem Staging“ (Werte der 82 Patienten nicht genau aufgeschlüsselt	Aussagen zur Ausbreitungsdiagnostik nicht verwertbar	2+

Artikel
(Autor, Jahr, Journal)

Studientyp,
prospektiv/
retrospektiv

Anzahl der Patienten

Patientenmerkmale

Diagnost. Intervention

Referenz-Standard

Ergebnisse

(Testgüte-Parameter)

Bemerkungen

Evidenz-Niveau
(SIGN)

Philip,
2005

Prospektive Kohorte, konsekutiver Patienteneinschluss

408

Vorstellig zur Diagnostik bei erhöhtem PSA (2,5-10 ng/ml)

DRE

Histologie aus Biopsie (408 Patienten) oder aus Prostatektomie-Präparat (82 Patienten)

Prävalenz: 152 bioptisch bestätigte PCAs von 408 Patienten (37%)

Testgüte-Parameter für Primärdiagnose PCA:

Sensitivität 61%

Spezifität 60%

PPW* 47%

NPW** 72%

„keine signifikante Korrelation zwischen DRE- und Biopsie-Stadium“

„sehr schlechte Übereinstimmung zwischen DRE und pathologischem Staging“ (Werte der 82 Patienten nicht genau aufgeschlüsselt

Aussagen zur Ausbreitungsdiagnostik nicht verwertbar

5.1 EvT 5.9

Artikel (Autor, Jahr, Journal)	Studientyp, prospektiv/ retrospektiv	Anzahl der Patienten	Patientenmerkmale	Diagnost. Intervention	Referenz-Standard	Ergebnisse (Testgüte-Parameter)	Bemerkungen	Evidenz-Niveau (SIGN)
Lavoipierre, 1998	Prospektive Kohorte	256	Vorstellig wegen auffälligem DRE-Befund (17%) oder erhöhtem PSA (46%) oder beidem (35%) oder Familienanamnese Patienteneinschluss konsekutiv	TRUS Doppler- vs. Graustufen-Technik	Histologie aus Biopsie (gezielte und ungezielte Entnahme)	Prävalenz: 100 diagnostizierte PCAs (39%) Für Graustufen-Technik: Sensitivität 75% Spezifität 40% PPW* 45% NPW** 72% Für Doppler-Technik: Sensitivität 76% Spezifität 38% PPW* 44% NPW** 71% Kombinierte Techniken: Sensitivität 60% Spezifität 56% PPW* 47%	Trotz Datenlage empfehlen Autoren die zusätzliche Anwendung von Doppler-Diagnostik bei unklaren Läsionen und betonen die Notwendigkeit von ungezielten Biopsien auch aus nicht suspekten Areal Diagnostische Kriterien genau definiert	2++
Halpern, 2000	Prospektive Kohorte	251	Vorstellig wegen erhöhtem PSA (> 4 ng/mL) in 76% der Fälle, übrige Patienten nicht näher charakterisiert Unklarer Patienteneinschluss (konsekutiv?	TRUS, Doppler- vs. Graustufen-Technik	Histologie aus Biopsie (gezielte und ungezielte Entnahme)	Prävalenz: 85 diagnostizierte PCAs (34%) Für Graustufen-Technik: Sensitivität 44% Spezifität 74% PPW* 21% NPW** 89% Für Doppler-Technik: Sensitivität 27% Spezifität 77% PPW* 16% NPW** 87% Höhere Werte für Sensitivität und Spezifität für sonographie-erfahrene Radiologen im Vergleich zu sonographie-unerfahrenen Urologen Multivariate Analyse: Wahrscheinlichkeit für positive Biopsie ist höher in sonographisch auffälligen Arealen (beide Techniken)	Ähnlich niedrige Werte für beide Verfahren, Autoren schließen, dass sonographisch auffällige Areale bioptiert werden sollten, Erfahrung in der sonographischen Diagnostik geht mit besseren Testgüte-Parametern einher Diagnostische Kriterien nicht angegeben („abnormal“)	2+

Artikel
(Autor, Jahr, Journal)

Studientyp,
prospektiv/
retrospektiv

Anzahl der Patienten

Patientenmerkmale

Diagnost. Intervention

Referenz-Standard

Ergebnisse

(Testgüte-Parameter)

Bemerkungen

Evidenz-Niveau
(SIGN)

Lavoipierre,
1998

Prospektive Kohorte

256

Vorstellig wegen auffälligem DRE-Befund (17%) oder erhöhtem PSA (46%) oder beidem (35%) oder Familienanamnese

Patienteneinschluss konsekutiv

TRUS Doppler- vs. Graustufen-Technik

Histologie aus Biopsie (gezielte und ungezielte Entnahme)

Prävalenz: 100 diagnostizierte PCAs (39%)

Für Graustufen-Technik:

Sensitivität 75%

Spezifität 40%

PPW* 45%

NPW** 72%

Für Doppler-Technik:

Sensitivität 76%

Spezifität 38%

PPW* 44%

NPW** 71%

Kombinierte Techniken:

Sensitivität 60%

Spezifität 56%

PPW* 47%

Trotz Datenlage empfehlen Autoren die zusätzliche Anwendung von Doppler-Diagnostik bei unklaren Läsionen und betonen die Notwendigkeit von ungezielten Biopsien auch aus nicht suspekten Areal

Diagnostische Kriterien genau definiert

2++

Halpern,
2000

Prospektive Kohorte

251

Vorstellig wegen erhöhtem PSA (> 4 ng/mL) in 76% der Fälle, übrige Patienten nicht näher charakterisiert

Unklarer Patienteneinschluss (konsekutiv?

TRUS, Doppler- vs. Graustufen-Technik

Histologie aus Biopsie (gezielte und ungezielte Entnahme)

Prävalenz: 85 diagnostizierte PCAs (34%)

Für Graustufen-Technik:

Sensitivität 44%

Spezifität 74%

PPW* 21%

NPW** 89%

Für Doppler-Technik:

Sensitivität 27%

Spezifität 77%

PPW* 16%

NPW** 87%

Höhere Werte für Sensitivität und Spezifität für sonographie-erfahrene Radiologen im Vergleich zu sonographie-unerfahrenen Urologen

Multivariate Analyse: Wahrscheinlichkeit für positive Biopsie ist höher in sonographisch auffälligen Arealen (beide Techniken)

Ähnlich niedrige Werte für beide Verfahren, Autoren schließen, dass sonographisch auffällige Areale bioptiert werden sollten, Erfahrung in der sonographischen Diagnostik geht mit besseren Testgüte-Parametern einher

Diagnostische Kriterien nicht angegeben („abnormal“)

Artikel (Autor, Jahr)/ Studientyp	Anzahl der Patienten/ Patientenmerkmale	Intervention/ ggf. Nachverfolgung	Vergleichsintervention Referenzstandard	Outcomes	Ergebnisse	Bemerkungen	Evidenzniveau SIGN
Testgüteparameter der Graustufensonographie der Prostata + ggf. Dopplerflowmessung
Lee H.Y. et al, 2009 Korea Retrospektive Fallserie	N=350 /114 konsekutive Pat. mit gezielten Biopsien Med. Alter 67,5J PSA>3ng/ml (med. 7,6ng/ml)	TRUS gesteuerte systematische + gezielte Biopsie (+1-2) von einem erfahrenen Untersucher HDI500 4-9Mhz + Dopplerflowmessung n= 236 Trainingsset : Entwicklung von Scoring-Kriterien für Auffälligkeit nach multivariater Analyse : - verstärkte Durchblutung (+1), unregelmäßige Begrenzung (+1) und nodulare oder Cluster-Auffälligkeit (+1) oder Ausdehnung der Auffälligkeit an die Außenseite der peripheren Zone (+1) n=114 Testset : Prüfen der Testgüteparameter	Nur TRUS syst. Biopsie (n=12) Referenzstandard: Histologie aus Biopsie	Positiver prädiktiver Wert der retrospektiv erhobenen Scoringkriterien für Auffälligkeit bei gezilter Biopsie vs. systematischer Biopsie	1.Anteil Karzinome gesamt: - Trainingsset. 43%, Testset 40% 2. PPV gesamt Testset gezielte+systematische Biopsie : 40% (46/114) nur systematische Biopsie : 30% (34/114) 3. PPV nach Scores Testset Score +4 gezielte + systematische Biopsie : 83% (19/23) nur systematische Biopsie : 52% (12/23) p=0,005 Score +3 gezielte+systematische Biopsie : 38% (13/34) nur systematische Biopsie : 32% (11/34) p=0,07 Score +2 35% (12/34) 27% (9/34) p<0,001 Score 0+1 n.s.		3
Tamsel R. et al, 2008 Retro-spektive Fallserie Türkei	N=830 Pat. Mittl. Alter 65J 45-80 5/2000-6/2004 Unklar, ob konsekutiv tPSA >4ng/ml	TRUS gesteuerte Biopsie mit zusätzlicher Probeentnahme suspekter Areale bei auffälliger TRUS (fokal hypo- oder , hyperechogen, auffällige Grenze, schlecht definierte Bereiche mit veränderten Graustufen	Nur TRUS sextant Biopise Untersuchung jeweils durch 2 erfahrene Untersucher mit Sonograhiegerät mit endorektaler Sonde 5-9 Mhz mit 18G Stanze, systematische (sextant) Biopsie mit 8 Stanzen Referenz- standard : Histologie aus Biopsie	Sensitivität Spezifität Positiver prädiktiver Wert negativer prädiktiver Wert Accuracy Für « auffällige TRUS »	Karzinome insgesamt : n=291 (35%) Auffällige TRUS gesamt : n=241 1.Sensitivität « auffällige TRUS »: 64% (185/241) 2. Spezifität « auffälliger TRUS » : 89% (483/539) 3. positiver prädiktiver Wert « auffälliger TRUS » : 76% 4. negativer prädiktiver Wert « auffälliger TRUS » : 82% 5. Accuracy : 80% Stratifiziert nach tPSA-Wert : Karzinomentdeckung TRUS in Gruppe 1 (4-9,9ng/ml) : 56% (22/39) Gruppe 2(10-19,9ng/ml) : 30% (28/93) Gruppe 3 (<20ng/ml) : 85% (135/159)		3

5.2 EvT 5.10

Artikel (Autor, Jahr)/ Studientyp	Anzahl der Patienten/ Patientenmerkmale	Intervention/ ggf. Nachverfolgung	Vergleichsintervention Referenzstandard	Outcomes	Ergebnisse	Bemerkungen	Evidenzniveau SIGN
Aigner F. et al, 2009 prospektive Fallserie/Kohortenstudie	n= 44 Screening-Freiwillige aus Innsbruck PSA-Wert > 1,25ng/ml Mittl. Alter 62J (42-76) und suspekte CEUS Befunde mit genannter Technik keine DRE	Bis zu 5 zielgerichtete Biopisen nach CEUS mit cadence-contrast pulse sequencing (CPE), niedriger mechanischer Index (MI 0,14) mit Freq. von 5 Mhz mit SonoVue Score : 1. schnelle Kontrastanreicherung (15-20s) 2. erhöhte Kontrastanreicherung 3. Asymmetrische Darstellung der intraprostatischen Gefäße	Systematische Biopsie mittels TRUS mit Sequoia mit Sonde EV8C$, Freq. 8 Mhz Fokus auf peripherer Zone, da bei Screening kaum Ca in Transitionszone. Referenz-standard : Histologie aus Biopsie	Anzahl entdeckter Karzinome Sensitivität Sepzifität Positiver prädiktiver Wert Negativer prädiktiver Wert	1. Anzahl entdeckter Karzinome Gesamt : 80% (35/44) Gleason Score 6,7 (5-10) CPE-CEUS gezielte Biopsie Sensitivität 100% Spezifität : nicht ermittelbar, da nur suspekte CPE-CEUS ausgewertet. 20% falsch Positive (n=9) NPV : nicht ermittelbar PPV 79,5% TRUS systematische Biopsie Sensitivität : 43% Spezifität : n.a. PPV : n.a. NPV : n.a.	Alle CEUS Untersuchungen durch einen erfahrenen Untersucher Systematische Biopsie mit TRUS durch Urologen ohne Kenntnis der anderen Befunde In der Publikation NPV und PPV nicht korrekt angegeben	3
Colleselli D. et al, 2007 Retrospektive Kohortenstudie Arbeitsgruppe Innsbruck	n=345 konsekutiv Pat. mit Prostatakarzinom Mittl. Alter 62,2J (41-75) mittl. tPSA 6,9 (1,32-43,4) asymptomatische Screening-Freiwillige	CEUS (mit SonoVue max. 4,8ml) mit gezielter Biopsie (« endfire »Sequioa 5-9Mhz) nur in peripherer Zone max. 5 von max. 2 hypoechogenen Zonen	TRUS mit systematischer Biopsie (n=10) (« endfire »Sequioa 5-9Mhz) Referenz-standard : Histologie aus Biopsie ?	Sensitivität CEUS-Biopsie vs TRUS systematische Biopsie für PCa-Entdeckung Stratifizierung der Ergebnisse anhand des Prostatavolumens	1. Sensitivität CEUS gezielte Biopsie: 77,1% (267/345) TRUS syst. Biopsie: 73,4% (252/345) n.s. 2. Sensitivität nach Volumen stratifiziert <20ml : CEUS gezielte Biopsie : 88% TRUS syst. Biopsie : 69% p<0,05 20-30ml : CEUS gezielte Biopsie : 80,8% TRUS syst. Biopsie : 70,4% p<0,05 Größere Volumina n.s.	Spezifität, positiver+negativer prädiktiver Wert n.a.	3
Mitterberger M. et al, 2007 Unizentrischer RCT Arbeitsgruppe Innsbruck	n=100 Screening-Freiwillige aus Innsbruck Alter im MIttel 52 (44-76) PSA 1,6-10 ng/ml Prostatavolumen 11-95ml Ausschluss : -Prostatitis bis zu 1 Mo vor Biopsie - aktive Infektion des Urintrakts - Kontraindikation gegen Kontrastmittel einschl. NYHA IV	n= 50 mit 5 gezielten Biopsien 18G nach kontrastmittelver-stärkter TRUS (= CEUS-TRUS) mit SonoVue aus hypervakulari-sierten Teilen der peripheren Prostatazone, nicht aus der Transitionszone Subj Grading : 0 = kein Farbsign. 1= niedr. Dichte 2= mittl. Dichte 3=hohe Dichte Sequioa 512 « endfire probe » Doppl. Freq. 9Mhz	n= 50 mit 10 systematischen Biopsien 18G (5 von jeder Seite, Basis, Mitte, Spitze medial, Spitze lateral, jewieils periphere Zone,+ Transitionszone) unter Standard-TRUS « biplane probe » grey-scale, 7,5 Mhz Referenz-standard : Histologie aus Biopsie, keine Nachverfolgung	1. Anzahl entdeckter Prostata-Karzinome 2. Prozentsatz positiver Biopsien im Verhältnis zur Gesamtzahl der Biopsien	Inzidenz PCa gesamt : 29% (29/100) Anzahl entdeckter Prostatakarzinome a. gezielt mit CEUS—TRUS 16% b. systematisch mit TRUS 13% p<0,04 2. Prozentsatz positiver Biopsien im Verhältnis zur Gesamtzahl a. gezielt mit CEUS-TRUS 15,6% b. Systematisch mit TRUS 6,8% p<0,001	Keine prospektive Powerberechnung Keine Angabe zu Sensitivität und Spezifität möglich, da keine falsch Negativen erhoben, .d.h. Vergleich mit Prostatektomiepräoparat fehlt. Die Autoren geben an, dass für CEUS-TRUS gezielte Biopsie die meisten nicht entdeckten Karzinom in der Apex der Prostata lagen. Verwendung von Sonographiegeräten unterschiedlicher Frequenz Hypoechogene Zonen nicht berücksichtigt bei gezielter Biopsie aufgrund spezifischer Screening-Population Alle Untersuchungen durch einen erfahrenen Untersucher, Lernkurve mit mind. 3 Mo angegeben	1-
Tang J. et al, 2007 unizentrische Fallserie/Kohortenstudie China	n= 66 Pat. prospektiv 6/06 – 2/07 mit auffälliger DRU (n=23), MRT, CT oder PSA-Wert < 10ng/ml (n=38) mittl. Alter 69,8+/-7,5J (49-83) PSA-Wert 1,3-38ng/ml Prostatavolumen im Mittel 45,4+/-26,9cm³	Biospie aus hypoechogenen Zonen (6-10Mhz endfiring probe 18G) CEUS mit end-firing probe 4-8Mhz Sequoia 512 mit contrast pulse sequence SonoVue mit niedriger akustischer Power 4 Kategorien : 1= keine Anreicherung 2=verstärkte Anreicherung 3=gleiche Anreicherung 4=verminderte Anreicherung im Vergleich zum umgebenden Gewebe	Systematische Biopsie nach TRUS / PDU PDU : 1= kein Signal 2=verstärktes Signal 3=gleiches Signal 4=vermindertes Signal im Vergleich zum umgebenden Gewebe Referenz-standard : Histologie aus Biopsie, Nachverfolgung benigne Befunde 3 Monate PSA-Kontrollen (alle o.B.)	Anzahl entdeckter Karzinome Sensitivität Spezifität Gleason Score der Karzinome cTNM	1. Anzahl entdeckter Karzinome Gesamt : 45% (30/66) a. CEUS Bei Peak-Intensität als Malignitätskriterium mit Cut-off 9,2dB Sensitivität : 65,2% Spezifität : 72,7% Mit relativer Peak-Intensität als Kriterium Sensitivität : 71,4% Spezifität : 81.8% b. TRUS/PDU bei erhöhtem Flow in peripherer hypoechogener Zone als Malignitätskriterium : Sensitivität 55,2% Spezifität : 53,8%	Eigentlich Explorationsstudie für Differenzierungskriterien benigne-maligne bei CEUS, deshalb als hohes Verzerrungsrisiko klassifiziert, da keine Validierungsstudie Autoren geben an, dass die genannten Kriterien objetiver als Dopplerflowmessungen zu erheben sind.	3
Taymoorian K. et al, 2007 Unizentrische Fallserie/ Kohortenstudie Berlin	n= 95 von 115 Pat. Mittl. Alter 66 (44-73) mit erhöhtem PSA.Wert (median 13,8, 4-48) und voraus-gegangener negativer Biopsie (bis zu 6x) 1/04-2/06 10 wegen Kontraindikationan ausgeschl, 9 wegen Lernkurve	2 zielgerichtete Biopsien mit biplaner Sonde 7,5Mhz aus suspekter hypervaskularisierter Zone in der Anflutungsphase oder hypochogener Zone in der späten Phase mit CEUS : Sonovue, Doppl. Freq. 3,6Mhz, eher niedr. akust. Power (MI<4), mit Sonogerät Aplio 80 6-9Mhz	TRUS, mit Sonogerät Aplio 80 6-9Mhz /PDU und systematische Bipsie mit biplaner Sonde 7,5Mhz Referenz-standard : Histologie aus Biopsie und Nachverfolgung 12 Mo benigner Befund – alle ohne Ca	Anzahl entdeckter Karzinome Sensitivität Spezifität	1. Anzahl entdeckter Karzinome Gesamt : 31,5% (30/95) a. CEUS : ohne Biopsie : 48 suspekte Läsionen Sensitivität : 100% Spezifität : 48% Nach Biopsie : Sensitivität : 80% (24/30) Spezifität : 100% ? b. systematische Biopsie TRUS/PDU : nur TRUS/PDU: Sensitivität : 0,7% (2/30) Nach Biopsie : Sensitivität : 26,6% (8/30) Spezifität : 100% ?		3
Wink M et al, 2008 Europäisches Multicenterprojekt Ergebnisse aus Innsbrucker Arbeitsgruppe	[Angegebene Patientenzahlen zu Publikationen zur gezielten Biopsie unter CEUS vs. systematischer Biopsie] ; alle aus Innsbrucker Arbeitsgruppe Frauscher 2002 n= 230 Screening-Freiwillige Kontrastmittel Levovist Pelzer 2005 n= 380 Screening-Freiwillige PSA-Wert 4-10ng/ml Mitterberger N= 690 Mittl. PSA-Wert 4,6 ng/ml Kontrastmittel Sonovenue (RCT Mitterberger siehe eigene Evidenztabelle)	Gezielte Biopsien nach CEUS –TRUS Sonokriterien nicht angegeben	Systematische Biopsien mit TRUS Referenz-standard : jeweils Histologie aus Biopsie	1. Anzahl entdeckter Karzinome 2. Anzahl positiver Biopsien im Verhältnis zur Gesamtzahl der Biopsien 3. Korrelation zum Gleason Score (Mitterberger)	Frauscher 2002 1. Entdeckte Karzinome Gesamt: 30% (69/230) CEUS gezielte Biopsie: 24,4% (56/230) Nur durch CEUS-Biopsie entdeckt: 7,4% (17/230) TRUS systematische Biopsie: 22,6%) Nur durch syst. Biopsie entdeckt: 5,6% (13/230) 2. Anteil positiver Biopsien CEUS gezielte Biopsie : 10,4% Systematische Biopsie : 5,3% P<0,05 Pelzer 2005 1. Entdeckte Karzinome Gesamt : 37,6% (143/380) CEUS gezielte Biopsie: 27,4% (104/380) Nur durch CEUS-Biopsie entdeckt: 10% (38/380) TRUS systematische Biopsie: 27,6% (105/380) Nur durch syst. Biopsie entdeckt : 10.2% (39/380) Anteil positiver Biopsien: CEUS gezielte Biopsie: 32,6% Systematische Biopsie: 17,9% p<0,01 Mitterberger 2007 1. Entdeckte Karzinome Gesamt: 32% (221/690) CEUS gezielte Biopsie: 26% (180/690) Nur durch CEUS-Biopsie entdeckt: 7,9% (55/690) TRUS systematische Biopsie: 24% (166/690) Nur durch syst. Biopsie entdeckt : 5,9% (41/690) 2. Anteil positiver Biopsien: k.A. 3. Gleason-Score Durch CEUS entdeckte Karzinome : Gleason-Score mind. 6 , Mittelwert 6,8 Durch system. Biopsie entdeckte Karzinome: Gleason-Score 4-6, Mittelwert 5,4 P<0,05	Jeweils am meisten entdeckte Karzinome durch Kombination der Verfahren Syst. Biopsie unter TRUS und Gezielte Bipsie mit CEUS Sonographische Kriterien für gezielte Biopsie aus den verschiedenen Publikationen nicht angegeben Nicht angegeben, ob prospektive oder retrospektive Serien Keine Validierung am Prostataktomie-Präparat Alle Arbeiten aus einer Arbeitsgruppe. Keine Angabe darüber, ob klinische relevante Karzinome entdeckt wurden. 2 publizierte Arbeiten von Mitterberger 2007 nicht aufgeführt – a) RCT n= 100 siehe eigene Evidenztabelle b) Fallserie n= 20 Anwendung Alphareduktasehemmer vor Untersuchung zu klein Ergebnisse der anderen Arbeitsgruppen zu (Seiten-)Lokalisation durch CEUS und CEUS zum Monitoring/Staging unter Therapie n.a.	2- bis 3
Yang J.C. et al, 2008 Fallserie/ Kohortenstudie	n= 115 konsekutive Pat. mittl. Alter 70 Jahre (47-85) PSA-Wert > 4ng/ml (4,3-387) DRU n.a. n=36 mit PSA-Wert 4-10ng/ml 6/07-5/08	CEUS mit SonoVue CEUS-Score : 0=keine Anreicherung 1= keine abnorme Anreicherung 2= intensive fokale Anreicherung 3= diffuse Anreicherung (2+3=positiv) 2 Biopsiestanzen (18G) aus allen CEUS-positiven hypoechogenen Zonen Gerät siehe Vergleichs-intervention	TRUS PDU (Power Doppler Ultra-sonography) mit 4-8Mhz « endfiring » probe Sequoia 512S PDU-Score : 0=keine abnorme Anreicherung 1=intensive fokale Anreicherung 2= diffuse Anreicherung (1+2= positiv) 2 Biopsiestanzen aus allen PDU positiven hypoechogenen Zonen + systematische Sextant-Biopsie (4 Proben v. peripherer Zone, 2 Proben v. Transitionszone) Referenz-standard : Histologie aus Biopsie	Anzahl entdeckter Karzinome 1. Sensitivität 2. Sepzifität 3. PPV (positiver prädiktiver Wert) 4. NPV (negativer prädiktiver Wert) 5. Accuracy (diagn. Sicherheit gesamt) im Hinblick auf Histologie aus Biopsie vs. gezielter Biopsie	Entdeckte Karzinome Gesamt : 55% (63/115) Sensitivität a. TRUS 51% (32/63) b. PDU 57% (36/63) c. CEUS 65% (41/63) 2. Spezifität a. TRUS 58% (30/52) b. PDU 65% (34/52) c. CEUS 83% (43/52) 3. PPV a. TRUS 59% (32/54) b. PDU 67% (36/54) c. CEUS 82% (41/50) 4. NPV a. TRUS 49% (30/61) b. PDU 56% (43/65) c. CEUS 66% (43/65) 5. Accuracy a. TRUS 54% (62/115) b. PDU 61% (70/115) c. CEUS 73% (84/115)	Kein Korrelat zu Prostatektomie	2+ bis 3

Artikel
(Autor, Jahr)/
Studientyp

Anzahl der Patienten/
Patientenmerkmale

Intervention/
ggf. Nachverfolgung

Vergleichsintervention
Referenzstandard

Outcomes

Ergebnisse

Bemerkungen

Evidenzniveau

SIGN

Aigner F. et al, 2009

prospektive

Fallserie/Kohortenstudie

n= 44

Screening-Freiwillige aus Innsbruck PSA-Wert > 1,25ng/ml

Mittl. Alter 62J (42-76)

und suspekte CEUS Befunde mit genannter Technik

keine DRE

Bis zu 5 zielgerichtete Biopisen nach

CEUS mit cadence-contrast pulse sequencing (CPE), niedriger mechanischer Index (MI 0,14) mit Freq. von 5 Mhz mit SonoVue

Score :

1. schnelle Kontrastanreicherung (15-20s)

2. erhöhte Kontrastanreicherung

3. Asymmetrische Darstellung der intraprostatischen Gefäße

Systematische Biopsie mittels TRUS mit Sequoia mit Sonde EV8C$, Freq. 8 Mhz

Fokus auf peripherer Zone, da bei Screening kaum Ca in Transitionszone.

Referenz-standard :

Histologie aus Biopsie

Anzahl entdeckter Karzinome

Sensitivität

Sepzifität

Positiver prädiktiver Wert

Negativer prädiktiver Wert

1. Anzahl entdeckter Karzinome

Gesamt : 80% (35/44)

Gleason Score 6,7 (5-10)

CPE-CEUS gezielte Biopsie

Sensitivität 100%

Spezifität : nicht ermittelbar, da nur suspekte CPE-CEUS ausgewertet.

20% falsch Positive (n=9)

NPV : nicht ermittelbar

PPV 79,5%

TRUS systematische Biopsie

Sensitivität : 43%

Spezifität : n.a.

PPV : n.a.

NPV : n.a.

Alle CEUS Untersuchungen durch einen erfahrenen Untersucher

Systematische Biopsie mit TRUS durch Urologen ohne Kenntnis der anderen Befunde

In der Publikation NPV und PPV nicht korrekt angegeben

Colleselli D. et al, 2007

Retrospektive Kohortenstudie

Arbeitsgruppe Innsbruck

n=345 konsekutiv

Pat. mit Prostatakarzinom

Mittl. Alter 62,2J (41-75)
mittl. tPSA 6,9 (1,32-43,4) asymptomatische Screening-Freiwillige

CEUS (mit SonoVue max. 4,8ml) mit gezielter Biopsie (« endfire »Sequioa 5-9Mhz) nur in peripherer Zone max. 5 von max. 2 hypoechogenen Zonen

TRUS mit systematischer Biopsie (n=10)
(« endfire »Sequioa 5-9Mhz)

Referenz-standard :

Histologie aus Biopsie ?

Sensitivität CEUS-Biopsie vs TRUS systematische Biopsie für PCa-Entdeckung

Stratifizierung der Ergebnisse anhand des Prostatavolumens

1. Sensitivität
CEUS gezielte Biopsie: 77,1% (267/345)
TRUS syst. Biopsie: 73,4% (252/345) n.s.

2. Sensitivität nach Volumen stratifiziert
<20ml :

CEUS gezielte Biopsie : 88%
TRUS syst. Biopsie : 69% p<0,05
20-30ml :
CEUS gezielte Biopsie : 80,8%
TRUS syst. Biopsie : 70,4% p<0,05

Größere Volumina n.s.

Spezifität, positiver+negativer prädiktiver Wert n.a.

Mitterberger M. et al, 2007

Unizentrischer

RCT

Arbeitsgruppe Innsbruck

n=100

Screening-Freiwillige aus Innsbruck

Alter im MIttel 52 (44-76)

PSA 1,6-10 ng/ml

Prostatavolumen 11-95ml

Ausschluss :

-Prostatitis bis zu 1 Mo vor Biopsie

- aktive Infektion des Urintrakts

- Kontraindikation gegen Kontrastmittel einschl. NYHA IV

n= 50 mit

5 gezielten Biopsien 18G nach kontrastmittelver-stärkter TRUS (= CEUS-TRUS) mit SonoVue aus hypervakulari-sierten Teilen der peripheren Prostatazone, nicht aus der Transitionszone

Subj Grading :

0 = kein Farbsign.

1= niedr. Dichte

2= mittl. Dichte

3=hohe Dichte

Sequioa 512 « endfire probe » Doppl. Freq. 9Mhz

n= 50 mit

10 systematischen Biopsien 18G

(5 von jeder Seite, Basis, Mitte, Spitze medial, Spitze lateral, jewieils periphere Zone,+ Transitionszone)

unter Standard-TRUS

« biplane probe »

grey-scale, 7,5 Mhz

Referenz-standard :

Histologie aus Biopsie, keine Nachverfolgung

1. Anzahl entdeckter Prostata-Karzinome

2. Prozentsatz positiver Biopsien im Verhältnis zur Gesamtzahl der Biopsien

Inzidenz PCa gesamt : 29% (29/100)

Anzahl entdeckter Prostatakarzinome

a. gezielt mit CEUS—TRUS

16%

b. systematisch mit TRUS

13% p<0,04

2. Prozentsatz positiver Biopsien im Verhältnis zur Gesamtzahl

a. gezielt mit CEUS-TRUS

15,6%

b. Systematisch mit TRUS

6,8% p<0,001

Keine prospektive Powerberechnung

Keine Angabe zu Sensitivität und Spezifität möglich, da keine falsch Negativen erhoben, .d.h. Vergleich mit Prostatektomiepräoparat fehlt.

Die Autoren geben an, dass für CEUS-TRUS gezielte Biopsie die meisten nicht entdeckten Karzinom in der Apex der Prostata lagen.

Verwendung von Sonographiegeräten unterschiedlicher Frequenz

Hypoechogene Zonen nicht berücksichtigt bei gezielter Biopsie aufgrund spezifischer Screening-Population

Alle Untersuchungen durch einen erfahrenen Untersucher, Lernkurve mit mind. 3 Mo angegeben

Tang J. et al, 2007

unizentrische

Fallserie/Kohortenstudie

China

n= 66 Pat. prospektiv

6/06 – 2/07

mit auffälliger DRU (n=23), MRT, CT oder PSA-Wert < 10ng/ml (n=38)

mittl. Alter 69,8+/-7,5J (49-83)

PSA-Wert 1,3-38ng/ml

Prostatavolumen im Mittel 45,4+/-26,9cm³

Biospie aus hypoechogenen Zonen (6-10Mhz endfiring probe 18G)

CEUS mit end-firing probe 4-8Mhz Sequoia 512 mit contrast pulse sequence SonoVue mit niedriger akustischer Power

4 Kategorien :

1= keine Anreicherung

2=verstärkte Anreicherung

3=gleiche Anreicherung

4=verminderte Anreicherung im Vergleich zum umgebenden Gewebe

Systematische Biopsie nach

TRUS / PDU

PDU :

1= kein Signal

2=verstärktes Signal

3=gleiches Signal

4=vermindertes Signal im Vergleich zum umgebenden Gewebe

Referenz-standard : Histologie aus Biopsie,

Nachverfolgung benigne Befunde 3 Monate PSA-Kontrollen (alle o.B.)

Anzahl entdeckter Karzinome

Sensitivität

Spezifität

Gleason Score der Karzinome

cTNM

1. Anzahl entdeckter Karzinome

Gesamt : 45% (30/66)

a. CEUS

Bei Peak-Intensität als Malignitätskriterium mit Cut-off 9,2dB

Sensitivität : 65,2%

Spezifität : 72,7%

Mit relativer Peak-Intensität als Kriterium

Sensitivität : 71,4%

Spezifität : 81.8%

b. TRUS/PDU

bei erhöhtem Flow in peripherer hypoechogener Zone als Malignitätskriterium :

Sensitivität 55,2%

Spezifität : 53,8%

Eigentlich Explorationsstudie für Differenzierungskriterien benigne-maligne bei CEUS, deshalb als hohes Verzerrungsrisiko klassifiziert, da keine Validierungsstudie

Autoren geben an, dass die genannten Kriterien objetiver als Dopplerflowmessungen zu erheben sind.

Taymoorian K. et al, 2007

Unizentrische Fallserie/
Kohortenstudie

Berlin

n= 95 von 115 Pat.

Mittl. Alter 66 (44-73) mit erhöhtem PSA.Wert (median 13,8, 4-48) und voraus-gegangener negativer Biopsie

(bis zu 6x)

1/04-2/06

10 wegen Kontraindikationan ausgeschl, 9 wegen Lernkurve

2 zielgerichtete Biopsien mit biplaner Sonde 7,5Mhz aus suspekter hypervaskularisierter Zone in der Anflutungsphase oder hypochogener Zone in der späten Phase mit CEUS : Sonovue, Doppl. Freq. 3,6Mhz, eher niedr. akust. Power (MI<4), mit Sonogerät Aplio 80 6-9Mhz

TRUS, mit Sonogerät Aplio 80 6-9Mhz /PDU und systematische Bipsie mit biplaner Sonde 7,5Mhz

Referenz-standard :

Histologie aus Biopsie und

Nachverfolgung 12 Mo benigner Befund – alle ohne Ca

Anzahl entdeckter Karzinome

Sensitivität

Spezifität

1. Anzahl entdeckter Karzinome

Gesamt : 31,5% (30/95)

a. CEUS :

ohne Biopsie : 48 suspekte Läsionen

Sensitivität : 100%

Spezifität : 48%

Nach Biopsie :

Sensitivität : 80% (24/30)

Spezifität : 100% ?

b. systematische Biopsie TRUS/PDU :

nur TRUS/PDU:

Sensitivität : 0,7% (2/30)

Nach Biopsie :

Sensitivität : 26,6% (8/30)

Spezifität : 100% ?

Wink M et al, 2008

Europäisches Multicenterprojekt

Ergebnisse aus Innsbrucker Arbeitsgruppe

[Angegebene Patientenzahlen zu Publikationen zur gezielten Biopsie unter CEUS vs. systematischer Biopsie] ;

alle aus Innsbrucker Arbeitsgruppe

Frauscher 2002

n= 230 Screening-Freiwillige

Kontrastmittel Levovist

Pelzer 2005

n= 380

Screening-Freiwillige

PSA-Wert 4-10ng/ml

Mitterberger

N= 690

Mittl. PSA-Wert 4,6 ng/ml

Kontrastmittel Sonovenue

(RCT Mitterberger siehe eigene Evidenztabelle)

Gezielte Biopsien nach CEUS –TRUS

Sonokriterien nicht angegeben

Systematische Biopsien mit TRUS

Referenz-standard :

jeweils

Histologie aus Biopsie

1. Anzahl entdeckter Karzinome

2. Anzahl positiver Biopsien im Verhältnis zur Gesamtzahl der Biopsien

3. Korrelation zum Gleason Score (Mitterberger)

Frauscher 2002

1. Entdeckte Karzinome

Gesamt: 30% (69/230)

CEUS gezielte Biopsie: 24,4% (56/230)

Nur durch CEUS-Biopsie entdeckt: 7,4% (17/230)

TRUS systematische Biopsie: 22,6%)

Nur durch syst. Biopsie entdeckt:

5,6% (13/230)

2. Anteil positiver Biopsien

CEUS gezielte Biopsie : 10,4%

Systematische Biopsie : 5,3%

P<0,05

Pelzer 2005

1. Entdeckte Karzinome

Gesamt : 37,6% (143/380)

CEUS gezielte Biopsie: 27,4% (104/380)

Nur durch CEUS-Biopsie entdeckt: 10% (38/380)

TRUS systematische Biopsie: 27,6% (105/380)

Nur durch syst. Biopsie entdeckt : 10.2% (39/380)

Anteil positiver Biopsien:

CEUS gezielte Biopsie: 32,6%

Systematische Biopsie: 17,9% p<0,01

Mitterberger 2007

1. Entdeckte Karzinome

Gesamt: 32% (221/690)

CEUS gezielte Biopsie: 26% (180/690)

Nur durch CEUS-Biopsie entdeckt:

7,9% (55/690)

TRUS systematische Biopsie: 24% (166/690)

Nur durch syst. Biopsie entdeckt :

5,9% (41/690)

2. Anteil positiver Biopsien: k.A.

3. Gleason-Score

Durch CEUS entdeckte Karzinome : Gleason-Score mind. 6 , Mittelwert 6,8

Durch system. Biopsie entdeckte Karzinome:

Gleason-Score 4-6, Mittelwert 5,4

P<0,05

Jeweils am meisten entdeckte Karzinome durch Kombination der Verfahren

Syst. Biopsie unter TRUS und Gezielte Bipsie mit CEUS

Sonographische Kriterien für gezielte Biopsie aus den verschiedenen Publikationen nicht angegeben

Nicht angegeben, ob prospektive oder retrospektive Serien

Keine Validierung am Prostataktomie-Präparat

Alle Arbeiten aus einer Arbeitsgruppe.

Keine Angabe darüber, ob klinische relevante Karzinome entdeckt wurden.

2 publizierte Arbeiten von Mitterberger 2007 nicht aufgeführt –

a) RCT n= 100 siehe eigene Evidenztabelle

b) Fallserie n= 20 Anwendung Alphareduktasehemmer vor Untersuchung zu klein

Ergebnisse der anderen Arbeitsgruppen zu (Seiten-)Lokalisation durch CEUS und CEUS zum Monitoring/Staging unter Therapie n.a.

2- bis 3

Yang J.C. et al, 2008

Fallserie/
Kohortenstudie

n= 115 konsekutive Pat.

mittl. Alter 70 Jahre (47-85)

PSA-Wert > 4ng/ml (4,3-387)

DRU n.a.

n=36 mit PSA-Wert 4-10ng/ml

6/07-5/08

CEUS mit SonoVue

CEUS-Score :

0=keine Anreicherung

1= keine abnorme Anreicherung

2= intensive fokale Anreicherung

3= diffuse Anreicherung

(2+3=positiv)

2 Biopsiestanzen (18G) aus allen CEUS-positiven hypoechogenen Zonen

Gerät siehe Vergleichs-intervention

TRUS

PDU (Power Doppler Ultra-sonography)

mit 4-8Mhz « endfiring » probe Sequoia 512S

PDU-Score :

0=keine abnorme Anreicherung

1=intensive fokale Anreicherung

2= diffuse Anreicherung (1+2= positiv)

2 Biopsiestanzen aus allen PDU positiven hypoechogenen Zonen + systematische Sextant-Biopsie (4 Proben v. peripherer Zone, 2 Proben v. Transitionszone)

Referenz-standard : Histologie aus Biopsie

Anzahl entdeckter Karzinome

1. Sensitivität

2. Sepzifität

3. PPV (positiver prädiktiver Wert)

4. NPV (negativer prädiktiver Wert)

5. Accuracy (diagn. Sicherheit gesamt)

im Hinblick auf Histologie aus Biopsie vs. gezielter Biopsie

Entdeckte Karzinome

Gesamt : 55% (63/115)

Sensitivität

a. TRUS 51% (32/63)
b. PDU 57% (36/63)

c. CEUS 65% (41/63)

2. Spezifität

a. TRUS 58% (30/52)
b. PDU 65% (34/52)

c. CEUS 83% (43/52)

3. PPV

a. TRUS 59% (32/54)
b. PDU 67% (36/54)

c. CEUS 82% (41/50)

4. NPV

a. TRUS 49% (30/61)
b. PDU 56% (43/65)

c. CEUS 66% (43/65)

5. Accuracy

a. TRUS 54% (62/115)
b. PDU 61% (70/115)

c. CEUS 73% (84/115)

Kein Korrelat zu Prostatektomie

2+ bis 3

5.2 EvT 5.11

Artikel (Autor, Jahr)/ Studientyp	Anzahl der Patienten/ Patientenmerkmale	Intervention/ ggf. Nachverfolgung	Vergleichsintervention Referenzstandard	Outcomes	Ergebnisse	Bemerkungen	Evidenzniveau SIGN
Cochlin et al., 2002 / prospektive Fallserie/ Kohortenstudie	100 konsekutive Pat. mit auffälliger DRU und/oder erhöhtem PSA	Elastographie Nachverfolgung für 1 Jahr	Grey-scale TRUS: 8,5 MHz Referenzstandard: Sextanten-biopsie: segmentale Biopsien des rechten und linken Lappens, Mitte und apikal	Sensitivität Spezifität PPV NPV	Elastographie: Sensitivität 51% (24/47), Spezifität 83% (44/53), PPV 72% (24/33), NPV 66% (44/67) TRUS: Sensitivität 54% (keine absoluten Angaben), Spezifität 73% (keine absoluten Angaben) Impact auf Management: N=3: Pat. mit nur durch Elastographie festgestelltem Karzinom (6,1% von insgesamt 19 Pat. mit festgestelltem Karzinom) N=2: Pat., in denen durch Elastographie zusätzliche krebsbefallene Bereiche festgestellt wurden, und in denen das Staging daraufhin verändert wurde (4,1% von insgesamt 49 Pat. mit festgestelltem Karzinom)	Keine Angaben bzgl. einer Verblindung bei der Auswertung	2+
Eggert et al., 2008 / RCT	351 Pat. mit auffälliger DRU und/oder erhöhtem PSA (> 4 ng/ml) Ausschluss-kriterien: vorangegangene Prostatabiopsie, operative Prostataeingriffe, akute Prostatitis innerhalb der letzten 4 Wo.	Elastographie-gruppe (n=189) Voluson 730 Ultraschallgerät TRUS+Biopsie (siehe rechts)	Kontrollgruppe (n=162) TRUS + Biopsie: 10 periphere Proben aus Apex, Mitte, Basis, mediale Anteile der Seitenlappen	Sensitivität Spezifität Vorhersage-genauigkeit der Elastographie vgl. mit TRUS	Elastographie: Sensitivität 44,5% (keine absoluten Angaben), Spezifität 89% (keine absoluten Angaben) TRUS: Sensitivität 39% (keine absoluten Angaben), Spezifität 78% (keine absoluten Angaben) Prostata-CA-Detektionsrate der Elastographiegruppe betrug 40,2% (76/189) ggü. 37,7% (61/162) in Kontrollgruppe (Unterschied n.s.= nicht signifikant). Detektionsraten - Subgruppenbetrachtung: Stadium T1c: Elastrogr. 30% vs. TRUS 25% (n.s.) Stadium T2: Detektionsraten gleich Stadium T3 u. T4: unabhängig vom bildgebenden Verfahren bestätigte sich bei allen Pat. klinischer Tastbefund	Keine Angaben zum Randomisierungsverfahren Homogene Verteilung der Gruppen	1+
Kamoi et al., 2008 / prospektive Kohortenstudie	107 konsekutive Pat. mit auffälliger DRU oder erhöhtem PSA (> 4 ng/ml) ohne vorherige Biopsie	Transrektale real-time Elastographie (TRTE): 7,5 MHz	TRUS Power Doppler Sonographie (PDUS) 8-Zylinder transperineale Ultraschall gesteuerte –Biopsie (konventionelle Sextanten-biopsie und lateraler Teil der peripheren Zone: jeweils ein Zylinder auf der rechten und linken Seite)	Sensitivität , Spezifität PPV, NPV Diagnostische Genauigkeit (Diagnostic accuracy, DA) ROC-Kurvenanalyse Odds ratio 95% KI	TRTE: Sensitivität 68% (27/40), Spezifität 81% (54/67), PPV 68% (27/40), NPV 81% (54/67), DA 76% (81/107) TRUS: Sensitivität 50% (20/40), Spezifität 85% (57/67), PPV 67% (20/30), NPV 74% (57/77), DA 72% (77/107) PDUS: Sensitivität 70% (28/40), Spezifität 75% (50/67), PPV 62% (28/45), NPV 81% (50/62), DA 73% (78/107) Unterschiede in Sensitivität zwischen TRUS und TRTE bzw. PDUS: signifikant (p=0,027 bzw. p=0,023) Unterschiede in Spezifität: n.s. Beste Kombination - PDUS+TRTE (aber Unterschiede nicht signifikant): Sensitivität 78% (31/40), Spezifität 73% (49/67), PPV 53% (31/59), NPV 84% (49/58), DA 75% (80/107) Kombination aller drei Ultraschalltechniken hatte keinen zusätzlichen diagnostischen Wert im Vergleich zur Kombination PDUS+TRTE ROC Kurvenanalyse: TRTE hat größte Fläche unter ROC curve – n.s. im Vgl. mit PUDS und TRUS	Rater waren verblindet ggü. den Ergebnissen der anderen Rater und Untersuchungen	2++
König et al, 2005 / prospektive Kohortenstudie	404 Pat. mit auffälliger DRU und/oder erhöhtem PSA	Elastographie Voluson 730 Ultraschallgerät 7,5 MHz	TRUS konventionelle Sextanten-biopsie	Sensitivität gesamt und differenziert nach Gleason Score	Elastographie: Sensitivität gesamt 84% (127/151) Sensitivität Gleason 2-4: 83,8% (31/37), Gleason 5-6: 86,7% (52/60), Gleason 7: 78,1% (25/32), Gleason >8: 86,4% (19/22). TRUS: Sensitivität gesamt 32,5% (49/151) Sensitivität Gleason 2-4: 21,6% (8/37), Gleason 5-6: 31,7% (19/60), Gleason 7: 46,9% (15/32), Gleason >8: 31,8% (7/22).	Pathologe war verblindet ggü. den Ergebnissen der Elastographie Inhomogene Pat.population (mehr als 50% hatte in der Vergangenheit > 1 Biopsie mit negativen Ergebnissen)	2+
Miyagawa et al, 2009 / prospektive Kohortenstudie	311 Pat. mit erhöhtem PSA (< 4 ng/ml und auffälliger DRU (tastbare noduläre Läsionen), und auffälligem TRUS (echoarme Läsionen) und auffälligem MRT (Läsionen mit niedriger Intensität auf T2-gewichteten Schnitten)	Elastographie alleine und Elastographie kombiniert mit TRUS 7,5 MHz	TRUS DRU 6- bis 8-Zylinder TRUS-gesteuerte Biopsie (18G Biopsienadel) 12 bis 14 Zylinder wurden in denjenigen Pat. gewonnen, die vorher bereits einer transrektalen Biopsie unterzogen wurden oder deren MRT Befund auf einen Tumor im vorderen Teil der Prostata hinwies (4 bis 6 Zylinder transperineal und 8 Zylinder transrektal)	Sensitivität gesamt und differenziert nach Gleason Score > 6 (Differenzierung nach Gleason Score nur für Elastographie)	Elastographie: Sensitivität 72,6% (69/95) Sensitivität Gleason 6: 69% (23/35), Gleason 7: 72% (21/29), Gleason 8: 81% (13/16), Gleason 9-10: 71% (10/14). Unterschiede n.s. TRUS: Sensitivität gesamt 59% (56/95) DRU: Sensitivität gesamt 37,9% (36/95) TRUS + Elastographie: Sensitivität gesamt 89,5% (85/95) Sensitivitäten von Elastographie und TRUS + Elastographie signifikant höher als Sensitivitäten von DRU oder TRUS (P<0,0001)	Elastographiebilder wurden verblindet ggü. den Biopsieresultaten ausgewertet	2+
Nelson et al, 2007 / prospektive Kohortenstudie	137 konsekutive Pat. mit auffälliger DRU oder erhöhtem PSA	Elastographie 6 MHz	TRUS (Gray-scale und Farb Doppler) Gezielte Biopsie der durch TRUS und Elastographie identifizierten auffälligen Bereichen sowie seitliche Sextantenbiopsie sowie bis zu 4 zusätzlichen parasagittalen Zylinderstanzen	Hauptziel der Studie: Vergleich zwischen systematischer Sextantenbiopsie vs. gezielter Biopsie mit Gray-scale TRUS, Farb Doppler TRUS und Elastographie Weitere Outcomes (hier relevant): Sensitivität, Spezifität, PPV, NPV (nur relative Angaben) OR bezogen auf gutartiges Gewebe für Gleason Score vs. pathologischer Befund im Ultraschall	Elastographie: Sensitivität 25%, Spezifität 86%, PPV 20%, NPV 88% Gleason 5-6 OR: 1,72, Gleason 7 OR: 3,36, Gleason 8 OR: 3,36, Gleason 9-10 OR: 4,11 Gray-scale TRUS: Sensitivität 16%, Spezifität 93%, PPV 26%, NPV 88% Gleason 5-6 OR: 2,14, Gleason 7 OR: 5,26, Gleason 8 OR: 7,68, Gleason 9-10 OR: 6,29 Farb Doppler: Sensitivität 29%, Spezifität 80%, PPV 18%, NPV 88% Gleason 5-6 OR: 0,96, Gleason 7 OR: 0,85, Gleason 8 OR: 4,12, Gleason 9-10 OR: 10,61 signifikanter Zusammenhang zwischen steigendem Gleason Score und allen drei Ultraschalluntersuchungen; Elastographie zeigte stärkere Korrelation mit höheren Gleason Scores, war aber im Gegensatz zum Farb Doppler ebenfalls mit niedrigerer Malignität assoziiert	Alle sonographischen Bilder nur von einem Reviewer ausgewertet Keine Angaben bezüglich einer Verblindung	2-
Salomon et al, 2008 / prospektive Fallserie	109 konsekutive Pat. mit histologisch nachgewiesenem Prostata-CA. Alle Pat. für eine radikale Prostatektomie vorgesehen.	Elastographie 7,5 MHz	Radikale Prostatektomie	Bezogen auf einzelne auffällige Areale („suspicious areas“): Sensitivität Spezifität PPV NPV Diagnostische Genauigkeit (keine absoluten Angaben) Stratifizierung der Sensitivität und Spezifität nach Regionen und Gleason Score	Elastographie: Sensitivität 75,4%, Spezifität 76,7%, PPV 87,8%, NPV 59%, Diagnostische Genauigkeit 76% Stratifizierung der Sensitivität nach Gleason Score: Gleason < 6: 74%, Gleason 7: 78%, Gleason >7: 93% Stratifizierung der Spezifität nach Gleason Score: Gleason < 6: 78%, Gleason 7: 80%, Gleason >7: 93% Elastographie dauerte 7-10 Min pro Patient	Bestmöglicher Referenzstandard Elastographie von einem Untersucher durchgeführt, der ggü. den klinischen Daten verblindet war. Pathologe verblindet ggü. den Ergebnissen der Elastographie.	2-3
Tsutsumi et al, 2007 / prospektive Fallserie	72 Pat. mit erhöhtem PSA, die zeitgleich mit einer TRUS-Biopsie einer Elastographie unterzogen wurden. Davon 51 Pat. in Analyse eingeschlossen Ausschlussgründe: verabreichte Hormontherapie, transurethrale OP in Vergangenheit, kleine Tumorläsionen (<0,5 ml), Elastographiebilder nicht auswertbar/schlechte Bedingungen bei Untersuchung	Elastographie EUB-6500 Ultraschallgerät 7,5 MHz Elastographie +TRUS	TRUS-Biopsie: Sextantenbiopsie bei der ersten Untersuchung und nachfolgende 12 transrektale und transperineale Zylinderbiopsie (keine gezielte Biopsie von in der Elastographie festgestellten positiven Arealen)	Detektionsrate Stratifizierung nach Tumorlokalisation, Gleason Score und Tumorstadium Sensitivität und PPV in Bezug auf die Tumolokalisation (anterior, Mitte, posterior)	Detektionsrate: N=15 Pat., in denen die Elastographiebefunde zu 100% mit der Tumorlokalisation übereinstimmte (29%); N=16 Pat., in denen die Elastographiebefunde mit der Tumorlokalisation übereinstimmte, aber auch falsch-positive Befunde vorhanden waren (31%); N=12 Pat., in denen die Elastographiebefunde mit der Tumorlokalisation übereinstimmte, aber auch falsch-negative Befunde vorhanden waren (24%); N=8 Pat., in denen die Elastographiebefunde nicht mit der Tumorlokalisation übereinstimmte, bzw. ein Tumor nicht lokalisiert werden konnte. TRUS+Elastographie lieferte eine Detektionsrate von 100% Stratifizierung nach Tumorlokalisation (bezogen auf positive Elastograhpiebefunde) Anterior: Sensitivität 94% (30/32), PPV 83% (30/36) Mitte: Sensitivität 76% (13/17), PPV 72% (13/18) Posterior: Sensitivität 57% (16/28), PPV 70% (16/23)	Auswertung der Bilder durch Ingenieur der ggü. die Tumorlokalisation verblindet war. Prostata Schnitte von Pathologen analysiert, der ggü. Ergebnissen der Elastographie verblindet war. Viele Pat. ausgeschlossen	3

Artikel
(Autor, Jahr)/
Studientyp

Anzahl der Patienten/
Patientenmerkmale

Intervention/
ggf. Nachverfolgung

Vergleichsintervention
Referenzstandard

Outcomes

Ergebnisse

Bemerkungen

Evidenzniveau

SIGN

Cochlin et al., 2002 / prospektive Fallserie/

Kohortenstudie

100 konsekutive Pat. mit auffälliger DRU und/oder erhöhtem PSA

Elastographie

Nachverfolgung für 1 Jahr

Grey-scale TRUS: 8,5 MHz

Referenzstandard: Sextanten-biopsie:

segmentale Biopsien des rechten und linken Lappens, Mitte und apikal

Sensitivität

Spezifität

PPV

NPV

Elastographie:

Sensitivität 51% (24/47), Spezifität 83% (44/53), PPV 72% (24/33), NPV 66% (44/67)

TRUS:

Sensitivität 54% (keine absoluten Angaben), Spezifität 73% (keine absoluten Angaben)

Impact auf Management:

N=3: Pat. mit nur durch Elastographie festgestelltem Karzinom (6,1% von insgesamt 19 Pat. mit festgestelltem Karzinom)

N=2: Pat., in denen durch Elastographie zusätzliche krebsbefallene Bereiche festgestellt wurden, und in denen das Staging daraufhin verändert wurde (4,1% von insgesamt 49 Pat. mit festgestelltem Karzinom)

Keine Angaben bzgl. einer Verblindung bei der Auswertung

Eggert et al., 2008 / RCT

351 Pat. mit auffälliger DRU und/oder erhöhtem PSA (> 4 ng/ml)

Ausschluss-kriterien: vorangegangene Prostatabiopsie, operative Prostataeingriffe, akute Prostatitis innerhalb der letzten 4 Wo.

Elastographie-gruppe (n=189)

Voluson 730 Ultraschallgerät

TRUS+Biopsie (siehe rechts)

Kontrollgruppe (n=162)

TRUS + Biopsie: 10 periphere Proben aus Apex, Mitte, Basis, mediale Anteile der Seitenlappen

Sensitivität

Spezifität

Vorhersage-genauigkeit der Elastographie vgl. mit TRUS

Elastographie:

Sensitivität 44,5% (keine absoluten Angaben), Spezifität 89% (keine absoluten Angaben)

TRUS:

Sensitivität 39% (keine absoluten Angaben), Spezifität 78% (keine absoluten Angaben)

Prostata-CA-Detektionsrate der Elastographiegruppe betrug 40,2% (76/189) ggü. 37,7% (61/162) in Kontrollgruppe (Unterschied n.s.= nicht signifikant).

Detektionsraten - Subgruppenbetrachtung:

Stadium T1c: Elastrogr. 30% vs. TRUS 25% (n.s.)

Stadium T2: Detektionsraten gleich

Stadium T3 u. T4: unabhängig vom bildgebenden Verfahren bestätigte sich bei allen Pat. klinischer Tastbefund

Keine Angaben zum Randomisierungsverfahren

Homogene Verteilung der Gruppen

Kamoi et al., 2008 / prospektive Kohortenstudie

107 konsekutive Pat. mit auffälliger DRU oder erhöhtem PSA (> 4 ng/ml) ohne vorherige Biopsie

Transrektale real-time Elastographie (TRTE): 7,5 MHz

TRUS

Power Doppler Sonographie (PDUS)

8-Zylinder transperineale Ultraschall gesteuerte –Biopsie (konventionelle Sextanten-biopsie und lateraler Teil der peripheren Zone: jeweils ein Zylinder auf der rechten und linken Seite)

Sensitivität , Spezifität PPV, NPV

Diagnostische Genauigkeit (Diagnostic accuracy, DA)

ROC-Kurvenanalyse

Odds ratio

95% KI

TRTE:

Sensitivität 68% (27/40), Spezifität 81% (54/67), PPV 68% (27/40), NPV 81% (54/67), DA 76% (81/107)

TRUS:

Sensitivität 50% (20/40), Spezifität 85% (57/67), PPV 67% (20/30), NPV 74% (57/77), DA 72% (77/107)

PDUS:

Sensitivität 70% (28/40), Spezifität 75% (50/67), PPV 62% (28/45), NPV 81% (50/62), DA 73% (78/107)

Unterschiede in Sensitivität zwischen TRUS und TRTE bzw. PDUS: signifikant (p=0,027 bzw. p=0,023)

Unterschiede in Spezifität: n.s.

Beste Kombination - PDUS+TRTE (aber Unterschiede nicht signifikant):

Sensitivität 78% (31/40), Spezifität 73% (49/67), PPV 53% (31/59), NPV 84% (49/58), DA 75% (80/107)

Kombination aller drei Ultraschalltechniken hatte keinen zusätzlichen diagnostischen Wert im Vergleich zur Kombination PDUS+TRTE

ROC Kurvenanalyse: TRTE hat größte Fläche unter ROC curve – n.s. im Vgl. mit PUDS und TRUS

Rater waren verblindet ggü. den Ergebnissen der anderen Rater und Untersuchungen

2++

König et al, 2005 / prospektive Kohortenstudie

404 Pat. mit auffälliger DRU und/oder erhöhtem PSA

Elastographie

Voluson 730 Ultraschallgerät 7,5 MHz

TRUS

konventionelle Sextanten-biopsie

Sensitivität gesamt und differenziert nach Gleason Score

Elastographie:

Sensitivität gesamt 84% (127/151)

Sensitivität Gleason 2-4: 83,8% (31/37), Gleason 5-6: 86,7% (52/60), Gleason 7: 78,1% (25/32), Gleason >8: 86,4% (19/22).

TRUS:

Sensitivität gesamt 32,5% (49/151)

Sensitivität Gleason 2-4: 21,6% (8/37), Gleason 5-6: 31,7% (19/60), Gleason 7: 46,9% (15/32), Gleason >8: 31,8% (7/22).

Pathologe war verblindet ggü. den Ergebnissen der Elastographie

Inhomogene Pat.population (mehr als 50% hatte in der Vergangenheit > 1 Biopsie mit negativen Ergebnissen)

Miyagawa et al, 2009 / prospektive Kohortenstudie

311 Pat. mit erhöhtem PSA (< 4 ng/ml und auffälliger DRU (tastbare noduläre Läsionen), und auffälligem TRUS (echoarme Läsionen) und auffälligem MRT (Läsionen mit niedriger Intensität auf T2-gewichteten Schnitten)

Elastographie alleine und Elastographie kombiniert mit TRUS

7,5 MHz

TRUS

DRU

6- bis 8-Zylinder TRUS-gesteuerte Biopsie (18G Biopsienadel)

12 bis 14 Zylinder wurden in denjenigen Pat. gewonnen, die vorher bereits einer transrektalen Biopsie unterzogen wurden oder deren MRT Befund auf einen Tumor im vorderen Teil der Prostata hinwies (4 bis 6 Zylinder transperineal und 8 Zylinder transrektal)

Sensitivität gesamt und differenziert nach Gleason Score > 6 (Differenzierung nach Gleason Score nur für Elastographie)

Elastographie:

Sensitivität 72,6% (69/95)

Sensitivität Gleason 6: 69% (23/35), Gleason 7: 72% (21/29), Gleason 8: 81% (13/16), Gleason 9-10: 71% (10/14).

Unterschiede n.s.

TRUS:

Sensitivität gesamt 59% (56/95)

DRU:

Sensitivität gesamt 37,9% (36/95)

TRUS + Elastographie:

Sensitivität gesamt 89,5% (85/95)

Sensitivitäten von Elastographie und TRUS + Elastographie signifikant höher als Sensitivitäten von DRU oder TRUS (P<0,0001)

Elastographiebilder wurden verblindet ggü. den Biopsieresultaten ausgewertet

Nelson et al, 2007 / prospektive Kohortenstudie

137 konsekutive Pat. mit auffälliger DRU oder erhöhtem PSA

Elastographie

6 MHz

TRUS (Gray-scale und Farb Doppler)

Gezielte Biopsie der durch TRUS und Elastographie identifizierten auffälligen Bereichen sowie seitliche Sextantenbiopsie sowie bis zu 4 zusätzlichen parasagittalen Zylinderstanzen

Hauptziel der Studie: Vergleich zwischen systematischer Sextantenbiopsie vs. gezielter Biopsie mit Gray-scale TRUS, Farb Doppler TRUS und Elastographie

Weitere Outcomes (hier relevant):

Sensitivität, Spezifität, PPV, NPV (nur relative Angaben)

OR bezogen auf gutartiges Gewebe für Gleason Score vs. pathologischer Befund im Ultraschall

Elastographie:

Sensitivität 25%, Spezifität 86%, PPV 20%, NPV 88%

Gleason 5-6 OR: 1,72, Gleason 7 OR: 3,36, Gleason 8 OR: 3,36, Gleason 9-10 OR: 4,11

Gray-scale TRUS:

Sensitivität 16%, Spezifität 93%, PPV 26%, NPV 88%

Gleason 5-6 OR: 2,14, Gleason 7 OR: 5,26, Gleason 8 OR: 7,68, Gleason 9-10 OR: 6,29

Farb Doppler:

Sensitivität 29%, Spezifität 80%, PPV 18%, NPV 88%

Gleason 5-6 OR: 0,96, Gleason 7 OR: 0,85, Gleason 8 OR: 4,12, Gleason 9-10 OR: 10,61

signifikanter Zusammenhang zwischen steigendem Gleason Score und allen drei Ultraschalluntersuchungen; Elastographie zeigte stärkere Korrelation mit höheren Gleason Scores, war aber im Gegensatz zum Farb Doppler ebenfalls mit niedrigerer Malignität assoziiert

Alle sonographischen Bilder nur von einem Reviewer ausgewertet

Keine Angaben bezüglich einer Verblindung

Salomon et al, 2008 / prospektive Fallserie

109 konsekutive Pat. mit histologisch nachgewiesenem Prostata-CA. Alle Pat. für eine radikale Prostatektomie vorgesehen.

Elastographie

7,5 MHz

Radikale Prostatektomie

Bezogen auf einzelne auffällige Areale („suspicious areas“):

Sensitivität

Spezifität

PPV

NPV

Diagnostische Genauigkeit

(keine absoluten Angaben)

Stratifizierung der Sensitivität und Spezifität nach Regionen und Gleason Score

Elastographie:

Sensitivität 75,4%, Spezifität 76,7%, PPV 87,8%, NPV 59%, Diagnostische Genauigkeit 76%

Stratifizierung der Sensitivität nach Gleason Score: Gleason < 6: 74%, Gleason 7: 78%, Gleason >7: 93%

Stratifizierung der Spezifität nach Gleason Score: Gleason < 6: 78%, Gleason 7: 80%, Gleason >7: 93%

Elastographie dauerte 7-10 Min pro Patient

Bestmöglicher Referenzstandard

Elastographie von einem Untersucher durchgeführt, der ggü. den klinischen Daten verblindet war.

Pathologe verblindet ggü. den Ergebnissen der Elastographie.

2-3

Tsutsumi et al, 2007 / prospektive Fallserie

72 Pat. mit erhöhtem PSA, die zeitgleich mit einer TRUS-Biopsie einer Elastographie unterzogen wurden.

Davon 51 Pat. in Analyse eingeschlossen

Ausschlussgründe: verabreichte Hormontherapie, transurethrale OP in Vergangenheit, kleine Tumorläsionen (<0,5 ml), Elastographiebilder nicht auswertbar/schlechte Bedingungen bei Untersuchung

Elastographie

EUB-6500 Ultraschallgerät

7,5 MHz

Elastographie
+TRUS

TRUS-Biopsie: Sextantenbiopsie bei der ersten Untersuchung und nachfolgende 12 transrektale und transperineale Zylinderbiopsie (keine gezielte Biopsie von in der Elastographie festgestellten positiven Arealen)

Detektionsrate

Stratifizierung nach Tumorlokalisation, Gleason Score und Tumorstadium

Sensitivität und PPV in Bezug auf die Tumolokalisation (anterior, Mitte, posterior)

Detektionsrate:

N=15 Pat., in denen die Elastographiebefunde zu 100% mit der Tumorlokalisation übereinstimmte (29%); N=16 Pat., in denen die Elastographiebefunde mit der Tumorlokalisation übereinstimmte, aber auch falsch-positive Befunde vorhanden waren (31%); N=12 Pat., in denen die Elastographiebefunde mit der Tumorlokalisation übereinstimmte, aber auch falsch-negative Befunde vorhanden waren (24%); N=8 Pat., in denen die Elastographiebefunde nicht mit der Tumorlokalisation übereinstimmte, bzw. ein Tumor nicht lokalisiert werden konnte.

TRUS+Elastographie lieferte eine Detektionsrate von 100%

Stratifizierung nach Tumorlokalisation (bezogen auf positive Elastograhpiebefunde)

Anterior: Sensitivität 94% (30/32), PPV 83% (30/36)

Mitte: Sensitivität 76% (13/17), PPV 72% (13/18)

Posterior: Sensitivität 57% (16/28), PPV 70% (16/23)

Auswertung der Bilder durch Ingenieur der ggü. die Tumorlokalisation verblindet war. Prostata Schnitte von Pathologen analysiert, der ggü. Ergebnissen der Elastographie verblindet war.

Viele Pat. ausgeschlossen

Drost_Cochrane_2019_Drost_EurUrol_2020

Drost FH, Osses DF, Nieboer D. et al. Prostate MRI, with or without MRI-targeted biopsy, and systematic biopsy for detecting prostate cancer. Cochrane Database Syst Rev. 2019 Apr 25;4(4):CD012663. doi: 10.1002/14651858.CD012663.pub2.

Drost FJH, Osses D, Nieboer D. et al. Prostate Magnetic Resonance Imaging, with or Without Magnetic Resonance Imaging-targeted Biopsy, and Systematic Biopsy for Detecting Prostate Cancer: A Cochrane Systematic Review and Meta-analysis. Eur Urol. 2020 Jan;77(1):78-94. doi: 10.1016/j.eururo.2019.06.023.

Link

https://pubmed.ncbi.nlm.nih.gov/31022301/

https://pubmed.ncbi.nlm.nih.gov/31326219/

AMSTAR 2 rating

moderate

Design

systematic review and meta-analysis

Sources

CENTRAL, MEDLINE, Embase, eight other databases and one trials register

(up to 31 July 2018)

Selection criteria

Inclusion criteria:

- cross-sectional study, if it investigated:

- the diagnostic accuracy of one or more of the index tests (MRI, MRI pathway (including MRI-targeted biopsy) or systematic biopsy) verified by the reference standard (template-guided biopsy), with each index test and reference standard performed in the same men or compared as in a randomised trial of test accuracy; or

- agreement evidence between the MRI pathway and systematic biopsy, with each test performed in the same men

- had to report on both MRI-positive and MRI-negative men

Exclusion criteria:

- when they could not extract a complete two-by-two table on a per-participant basis for the primary target condition, even after contacting the study authors

Outcome(s)

accuracy (pooled estimates of sensitivity and specificity): MRI, MRI-targeted biopsy, MRI pathway, systematic biopsy versus reference standard (template-guided biopsy)

agreement (number of target conditions identified - concordance and discordance - proportion of detected cases (total number of cancers) as the number of concordant positive results plus the number of discordant positive results of both tests, detection rate, pooled estimates of detection ratios): MRI pathway versus systematic biopsy

pooled proportions of prostate cancer not detected by systematic biopsy but only by the MRI pathway (added value MRI pathway) and pooled proportions of prostate cancer not detected by the MRI pathway but only by systematic biopsy (added value systematic biopsy)

negative predictive values (NPV) and positive predictive values (PPV)

Quality of evidence

methodological quality: Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool; Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidance for studies of diagnostic accuracy

- a considerable number of studies (test accuracy) had a high or unclear risk of bias in the participant selection (n = 9/18) and reference standard domains (n = 12/18)

- no risk of bias was present in the index test (n = 1/18) and flow and timing domains (n = 3/18)

- three out of 18 studies had applicability concerns because either they had selected an explicitly high-risk population or had used an alternative MRI-scale or MRI-positivity threshold (other than the default 5-point scale with an MRI-positivity threshold of 3/5 or more) (s. also Table 1 and Figure 4-6 within the publication)

- a considerable number of studies (agreement) (n = 13/25) had a high or unclear risk of bias in the participant selection domain (s. Figure 7 within the publication)

- the index test domain, a considerable number of studies (n = 15/25) had a high or unclear risk of bias in the performance of systematic biopsy but almost no risk of bias was present in the performance of the MRI pathway (n = 1/18)

- few studies had a high or unclear risk of bias in the flow and timing domain (n = 8/25)

- applicability concerns were present in 15 out of 25 studies, mainly because they used an alternative method to perform one of the index tests

- the quality of evidence for the main findings of this review was rated as low

Results

43 articles were eligible for inclusion (mainly from Western countries, of men aged 61 to 73 years)

- 18 studies in the diagnostic test accuracy analysis (n=15 on MRI, n=8 on MRI, MRI-targeted biopsy and the MRI pathway in the same men, n=4 on systematic biopsy)

including 6871 men (5075 were biopsy naïve and 1796 had a history of at least one prior negative biopsy)
13 prospective studies
5 retrospective studies

- 25 studies in the agreement analysis

including 6944 men (5353 were biopsy naïve and 1591 had a history of at least one prior negative biopsy)
18 prospective studies
7 retrospective studies

Population: men with a clinical suspicion of prostate cancer (based on PSA or digital rectal exam (DRE) outcome) in the biopsy-naïve or prior-negative biopsy setting (or a mix of both) - excluded were men with a previous diagnosis of prostate cancer

Table 1 Detecting ISUP grade 2 or higher prostate cancer by MRI, MRI-targeted biopsy, MRI-pathway and systematic biopsy (n=13,770)

	pooled sensitivity (95%CI)	pooled specificity (95%CI)	true / false positives per 1000 men (95%CI)	true / false negatives per 1000 men (95%CI)
Accuracy analysis: (comment: considerable heterogeneity in all index tests)
MRI compared to template-guided biopsy	0.91 (0.83-0.95) 12 studies, 3091 P (low certainty of evidence)	0.37 (0.29-0.46) 12 studies (low certainty of evidence)	273 (249-285) / 441 (378-497)*#	259 (203-322) / 27 (15-51)*#
MRI-targeted biopsy compared to template-guided biopsy	0.80 (0.69-0.87) 8 studies, 1553 P (low certainty of evidence)	0.94 (0.90-0.97) 8 studies (low certainty of evidence)	240 (207-261) / 42 (21-70)*	658 (630-679) / 60 (39-93)*
MRI pathway compared to template-guided biopsy	0.72 (0.60-0.82) 8 studies, 2257 P (low certainty of evidence)	0.96 (0.94-0.98) 8 studies (low certainty of evidence)	216 (180-246) / 28 (14-42)*	672 (658-686) / 84 (54-120)*
Systemic biopsy compared to template-guided biopsy	0.63 (0.19-0.93) 4 studies, 3421 P (low certainty of evidence)	1.00 (0.91-1.00) 4 studies (low certainty of evidence)	189 (57-279) / 0 (0-63)*	700 (637-700) / 111 (21-243)*
	pooled detection ratio (95%CI) (mixed population)	pooled detection ratio (95%CI) (prior-negative biopsy men)	pooled detection ratio (95%CI) (biopsy-naïve men)
Agreement analyses
MRI pathway to SB	1.12 (1.02-1.23) 25 studies, 6944 P	1.44 (1.19-1.75) 10 studies, 1564 P	1.05 (0.95-1.16) 20 studies, 5219 P
MRI pathway missed %(95%CI) less than SB:	12 (2-23)	44 (19-75)	5 (−5-16)

CI=confidence interval, ISUP: International Society of Urological Pathology, MRI=magnetic resonance imaging, P=participants, SB=systematic biopsy

*using a baseline prevalence of 30%

#for example: “In a population of 1000 men at risk for prostate cancer, where 300 men actually have clinically significant prostate cancer, MRI will correctly identify 273 men as having clinically significant prostate cancer but miss the remaining 27 men; for the 700 men that do not have clinically significant prostate cancer, MRI will correctly identify 259 as not having prostate cancer but will misclassify 441 men as having clinically significant prostate cancer.”

number needed to biopsy (NNB)

for systematic biopsy in addition to MRI-targeted biopsy:

- in biopsy-naïve men with a positive MRI:

grade ≥2 PCa detection: 20 (95 % CI 12-36)
grade ≥3 PCa: 27 (95% CI 16-45)

- in biopsy-naïve men with a negative MRI:

grade ≥2 PCa detection: 13 (95% CI 9-18)
grade ≥3 PCa: 33 (95% CI 18-63)

- in men with a prior negative biopsy and a positive MRI:

grade ≥2 PCa: 37 (95% CI 18-83)
grade ≥3 PCa: 83 (95% CI 31-250)

- in men with a prior negative biopsy and MRI-negative:

grade ≥2 PCa: 19 (95% CI 11-32)
grade ≥3 PCa: 31 (95% CI 16-63)

Table 2 Detecting ISUP grade 1 prostate cancer by MRI, MRI-targeted biopsy, MRI-pathway and systematic biopsy (n=10,051)

	pooled sensitivity (95%CI)	pooled specificity (95%CI)	Avoidable overdiagnosis per 1000 men (95%CI)
Accuracy analysis
MRI compared to template-guided biopsy	0.70 (0.59-0.80) 10 studies, 1764 P (low certainty of evidence)	0.27 (0.19-0.37) 10 studies (low certainty of evidence)	63 (42-86)
MRI-targeted biopsy compared to template-guided biopsy	0.51 (0.21-0.81) 5 studies, 497 P (low certainty of evidence)	1.00 (0.77-1.00) 5 studies (low certainty of evidence)	103 (40-166)
MRI pathway compared to template-guided biopsy	0.34 (0.19-0.53) 5 studies, 681 P (low certainty of evidence)	1.00 (0.90-1.00) 8 studies (low certainty of evidence)	139 (99-170)
Systemic biopsy compared to template-guided biopsy	0.55 (0.25-0.83) 4 studies, 3421 P (low certainty of evidence)	0.99 (0.81-1.00) 4 studies (low certainty of evidence)	95 (36-158)
	pooled detection ratio (95%CI) (mixed population)	pooled detection ratio (95%CI) (prior-negative biopsy men)	pooled detection ratio (95%CI) (biopsy-naïve men)
Agreement analyses
MRI pathway to SB (mixed population)	0.61 (0.52-0.71) 21 studies, 5442 P	0.62 (0.44-0.88) 8 studies, 1202 P	0.63 (0.54-0.74) 17 studies, 4079 P

Comments

Articles included in this study:

eighteen studies (test accuracy - index tests versus reference standard (template-guided biopsy):

- 15 studies on MRI (Abd-Alazeez 2014; Ahmed 2017; Dal Moro 2019; Distler 2017; Grey 2015; Hansen 2016a; Hansen 2018; Hansen 2017; Kesch 2017; Lawrence 2014; Mortezavi 2018; Muthuveloe 2016; Pepe 2013; Thompson 2016; Tsivian 2017);

- eight studies on MRI, MRI-targeted biopsy and the MRI pathway in the same men (Dal Moro 2019; Distler 2017; Hansen 2016a; Hansen 2017; Kesch 2017; Lawrence 2014; Mortezavi 2018; Pepe 2013);

- four studies: on systematic biopsy (Ahmed 2017; Nafie 2014; Nafie 2017; Ploussard 2014)

twenty-five studies (agreement between the MRI pathway and systematic biopsy in detecting prostate cancer): Alberts 2017; Boesen 2017a; Boesen 2018; Castellucci 2017; Chang 2017; Chen 2015; Cool 2016; Costa 2013; Delongchamps 2013; Filson 2016; Garcia Bennett 2017; Grönberg 2018; Jambor 2015; Jambor 2017; Kim 2017; Lee 2016; Lee 2017; Okcelik 2016; Panebianco 2015; Peltier 2015; Pokorny 2014; Rouvière 2019a; Say 2016; Tonttilla 2016; Van der Leest 2018)

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Abd-Alazeez 2014 {published and unpublished data}. Abd-Alazeez, M, Arya HU, Charman SC, Anastasiadis E, Freeman A, Emberton M, et al. The accuracy of multiparametric MRI in men with negative biopsy and elevated PSA level-Canit rule out clinically significant prostate cancer?. Urologic Oncology 2014;32(1):45.e17-45.e22.

Ahmed 2017 {published and unpublished data}. Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, et al. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet 2017;389(10071):815-22.

Alberts 2017 {published data only}. Alberts AR, Schoots IG, Bokhorst LP, Drost FH, Van Leenders GJ, Krestin GP, et al. Characteristics of prostate cancer found at fiSh screening in the European Randomized Study of Screening for Prostate Cancer Rotterdam: can we selectively detect high-grade prostate cancer with upfront multivariable risk stratification and magnetic resonance imaging?. European Urology 19 June 2017 [Epub ahead of print];S0302-2838(17):30514-6.

Boesen 2017a {published data only (unpublished sought but not used)}. Boesen L, Nørgaard N, Løgager V, Balslev I, Thomsen HS. A prospective comparison of selective multiparametric magnetic resonance imaging fusion-targeted and systematic transrectal ultrasound-guided biopsies for detecting prostate cancer in men undergoing repeated biopsies. Urologia Internationalis 2017;99(4):384-91.

Boesen 2018 {published and unpublished data}. Boesen L, Nørgaard N, Løgager V, Balslev I, Bisbjerg R, Thestrup K-C, Winther, et al. Assessment of the diagnostic accuracy of biparametric magnetic resonance imaging for prostate cancer in biopsy-naïve men the Biparametric MRI for Detection of Prostate Cancer (BIDOC) Study. JAMA Network Open 2018;1(2):e180219.

Castellucci 2017 {published and unpublished data}. Castellucci R, Linares Quevedo AI, Sánchez GómezFJ, Díez Rodríguez J, Cogorno L, Cogollos Acuña I, et al. Prospective nonrandomized study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasound-guided biopsy to magnetic resonance imaging with subsequent MRIguided biopsy in biopsy-naïve patients. Minerva Urologica e Nefrologica 2017;69(6):589-95.

Chang 2017 {published and unpublished data}. Chang CH, Chiu HC, Lin WC, Ho TL, Chang H, Chang YH, et al. The influence of serum prostate-specific antigen on the accuracy of magnetic resonance imaging targeted biopsy versus saturation biopsy in patients with previous negative biopsy. BioMed Research International 2017;2017:7617148.

Chen 2015 {published data only}. Chen J, Yi XL, Jiang LX, Wang R, Zhao JG, Li YH, et al. 3-tesla magnetic resonance imaging improves the prostate cancer detection rate in transrectral ultrasound‑guided biopsy. Experimental and Therapeutic Medicine 2015;9(1):207-12.

Cool 2016 {published data only}. Cool DW, Romagnoli C, Izawa JI, Chin J, Gardi L, Tessier D, et al. Comparison of prostate MRI-3D transrectal ultrasound fusion biopsy for first-time and repeat biopsy patients with previous atypical small acinar proliferation. Canadian Urological Association Journal 2016;10(9-10):342-8.

Costa 2013 {published data only}. Costa DN, Bloch BN, Yao DF, Sanda MG, Ngo L, Genega EM, et al. Diagnosis of relevant prostate cancer using supplementary cores from magnetic resonance imaging-prompted areas following multiple failed biopsies. Magnetic Resonance Imaging 2013;31(6):947-52.

Dal Moro 2019 {published and unpublished data}. Dal Moro F, Zecchini G, Morlacco A, Gardiman MP, Lacognata CS, Lauro A, et al. Does 1.5 T mpMRI play a definite role in detection of clinically significant prostate cancer? Findings from a prospective study comparing blind 24-core saturation and targeted biopsies with a novel data remodeling model. Aging Clinical and Experimental Research 2019;31(1):115-23.

Delongchamps 2013 {published data only}. Delongchamps NB, Peyromaure M, Schull A, Beuvon F, Bouazza N, Flam T, et al. Prebiopsy magnetic resonance imaging and prostate cancer detection: comparison of random and targeted biopsies. The Journal of Urology 2013;189(2):493-9.

Distler 2017 {published data only}. Distler FA, Radtke JP, Bonekamp D, Kesch C, Schlemmer HP, Wieczorek K, et al. The value of PSA density in combination with PI-RADS for the accuracy of prostate cancer prediction. The Journal of Urology 2017;198(3):575-82.

Filson 2016 {published data only}. Filson CP, Natarajan S, Margolis DJ, Huang J, Lieu P, Dorey FJ, et al. Prostate cancer detection with magnetic resonanceultrasound fusion biopsy: the role of systematic and targeted biopsies. Cancer 2016;122(6):884-92.

Garcia Bennett 2017 {published and unpublished data}. Garcia Bennett J, Vilanova JC, Guma Padro J, Parada D, Conejero A. Evaluation of MR imaging-targeted biopsies of the prostate in biopsy naïve patients. A single centre study. Diagnostic and Interventional Imaging 2017;98(10):677-84.

Grey 2015 {published and unpublished data}. Grey AD, Chana MS, Popert R, Wolfe K, Liyanage SH, Acher PL. Diagnostic accuracy of magnetic resonance imaging (MRI) prostate imaging reporting and data system (PI-RADS) scoring in a transperineal prostate biopsy setting. BJU International 2015;115(5):728-35.

Grönberg 2018 {published and unpublished data}. Grönberg H, Eklund M, Picker W, Aly M, Jäderling F, Adolfsson J, et al. Prostate cancer diagnostics using a combination of the Stockholm3 blood test and multiparametric magnetic resonance imaging. European Urology 2018;74(6):722-8.

Hansen 2016a {published and unpublished data}. Hansen N, Patruno G, Wadhwa K, Gaziev G, Miano R, Barrett T, et al. Magnetic resonance and ultrasound image fusion supported transperineal prostate biopsy using the Ginsburg protocol: technique, learning points, and biopsy results. Eurpean Urology 2016;70(2):332-40.

Hansen 2017 {published data only}. Hansen NL, Kesch C, Barrett T, Koo B, Radtke JP, Bonekamp D, et al. Multicentre evaluation of targeted and systematic biopsies using magnetic resonance and ultrasound image-fusion guided transperineal prostate biopsy in patients with a previous negative biopsy. BJU International 2017;120(5):631-8.

Hansen 2018 {published data only}. Hansen NL, Barrett T, Kesch C, Pepdjonovic L, Bonekamp D, O'SullivanR, et al. Multicentre evaluation of magnetic resonance imaging supported transperineal prostate biopsy in biopsy naïve men with suspicion of prostate cancer. BJU International 2018;122(1):40-9.

Jambor 2015 {published data only}. Jambor I, Kähkönen E, Taimen P, Merisaari H, Saunavaara J, Alanen K, et al. Prebiopsy multiparametric 3T prostate MRI in patients with elevated PSA, normal digital rectal examination, and no previous biopsy. Journal of Magnetic Resonance Imaging 2015;41(5):1394-404.

Jambor 2017 {published data only}. Jambor I, Boström PJ, Taimen P, Syvänen K, Kähkönen E, Kallajoki M, et al. Novel biparametric MRI and targeted biopsy improves risk stratification in men with a clinical suspicion of prostate cancer (IMPROD Trial). Journal of Magnetic Resonance Imaging 2017;46(4):1089-95.

Kesch 2017 {published and unpublished data}. Kesch C, Radtke JP, Popeneciu IV, Gasch C, DieOenbacher SC, Klein T, et al. TOP: prospective evaluation of a volume based, computer assisted method for transperineal optimized prostate biopsy. Urologia Internationalis 2017;99(2):149-55.

Kim 2017 {published and unpublished data}. Kim EH, Weaver JK, Shetty AS, Vetter JM, Andriole GL, Strope SA. Magnetic resonance imaging provides added value to the prostate cancer prevention trial risk calculator for patients with estimated risk of high-grade prostate cancer less than or equal to 10%. Urology 2017;102:183-9.

Lawrence 2014 {published data only}. Lawrence EM, Tang SY, Barrett T, Koo B, Goldman DA, Warren AY, et al. Prostate cancer: performance characteristics of combined T2W and DW-MRI scoring in the setting of template transperineal re-biopsy using MR-TRUS fusion. European Radiology 2014;24(7):1497-505.

Lee 2016 {published and unpublished data}. Lee DH, Nam JK, Park SW, Lee SS, Han JY, Lee SD, et al. Visually estimated MRI targeted prostate biopsy could improve the detection of significant prostate cancer in patients with a PSA level. Yonsei Medical Journal 2016;57(3):565-71.

Lee 2017 {published and unpublished data}. Lee DH, Nam JK, Lee SS, Han JY, Lee JW, Chung MK, et al. Comparison of multiparametric and biparametric MRI in first round cognitive targeted prostate biopsy in patients with PSA levels under 10 ng/mL. Yonsei Medical Journal 2017;58(5):994-9.

Mortezavi 2018 {published data only}. Mortezavi A, Märzendorfer O, Donati OF, Rizzi G, Rupp NJ, WettsteinMS, et al. Diagnostic accuracy of multiparametric magnetic resonance imaging and fusion guided targeted biopsy evaluated by transperineal template saturation prostate biopsy for the detection and characterization of prostate cancer. Journal of Urology 2018;200(2):309-18.

Muthuveloe 2016 {published and unpublished data}. Muthuveloe D, Telford R, Viney R, Patel P. The detection and upgrade rates of prostate adenocarcinoma following transperineal template-guided prostate biopsy – a tertiary referral centre experience. Central European Journal of Urology 2016;69(1):42-7.

Nafie 2014 {published data only}. Nafie S, Mellon JK, Dormer JP, Khan MA. The role of transperineal template prostate biopsies in prostate cancer diagnosis in biopsy naïve men with PSA less than 20 ng mL-1. Prostate Cancer and Prostatic Diseases 2014;17(2):170-3.

Nafie 2017 {published data only}. Nafie S, Wanis M, Khan M. The eOicacy of transrectal ultrasound guided biopsy versus transperineal template biopsy of the prostate in diagnosing prostate cancer in men with previous negative transrectal ultrasound guided biopsy. Urology Journal 2017;14(2):3008-12.

Okcelik 2016 {published and unpublished data}. Okcelik S, Soydan H, Ates F, Berber U, Saygin H, Sonmez G, et al. Evaluation of PCA3 and multiparametric MRI's: collective benefits before deciding initial prostate biopsy for patients with PSA level between 3-10ng/mL. International Brazillian Journal of Urology 2016;42(3):449-55.

Panebianco 2015 {published and unpublished data}. Panebianco V, Barchetti F, Sciarra A, Ciardi A, Indino EL, Papalia R, et al. Multiparametric magnetic resonance imaging vs. standard care in men being evaluated for prostate cancer: a randomized study. Urologic Oncology 2015;33(1):17.e1-17.e7.

Peltier 2015 {published data only}. Peltier A, Aoun F, Lemort M, Kwizera F, Paesmans M, Van Velthoven R. MRI-targeted biopsies versus systematic transrectal ultrasound guided biopsies for the diagnosis of localized prostate cancer in biopsy naïve men. Biomed Research International 2015;2015:571708.

Pepe 2013 {published data only (unpublished sought but not used)}. Pepe P, Garufi A, Priolo G, Candiano G, Pietropaolo F, Pennisi M, et al. Prostate cancer detection at repeat biopsy: can pelvic phased array multiparametric MRI replace saturation biopsy?. Anticancer Research 2013;33(3):1195-200.

Ploussard 2014 {published data only}. Ploussard G, Nicolaiew N, Marchand C, Terry S, Vacherot F, Vordos D, et al. Prospective evaluation of an extended 21-core biopsy scheme as initial prostate cancer diagnostic strategy. European Urology 2014;65(1):154-61.

Pokorny 2014 {published and unpublished data}. Pokorny MR, De Rooij M, Duncan E, Schröder FH, Parkinson R, Barentsz JO, et al. Prospective study of diagnostic accuracy comparing prostate cancer detection by transrectal ultrasoundguided biopsy versus magnetic resonance (MR) imaging with subsequent MR-guided biopsy in men without previous prostate biopsies. European Urology 2014;66(1):22-9.

Rouvière 2019a {published data only}. Rouvière O, Puech P, Renard-Penna R, Claudon M, Roy C, Mège-Lechavallier F, et al. MRI-FIRST Investigators. Use of prostate systematic and targeted biopsy on the basis of multiparametric MRI in biopsy-naïve patients (MRI-FIRST): a prospective, multicentre, paired diagnostic study. Lancet Oncology 2019;20(1):100-9.

Say 2016 {published data only}. SayRK. MRI-ultrasound fusion targeted biopsy in men with prior negative prostate biopsy for prostate cancer [PhD thesis]. Vol. 2078, New Haven, CT: Yale Medicine Thesis Digital Library, 2016. [elischolar.library.yale.edu/ymtdl/2078]

Thompson 2016 {published and unpublished data}. Thompson JE, Van Leeuwen PJ, Moses D, Shnier R, Brenner P, Delprado W, et al. The diagnostic performance of multiparametric magnetic resonance imaging to detect significant prostate cancer. Journal of Urology 2016;195(5):1428-35.

Tonttilla 2016 {published and unpublished data}. Tonttila PP, Lantto J, Pääkkö E, Piippo U, Kauppila S, Lammentausta E, et al. Prebiopsy multiparametric magnetic resonance imaging for prostate cancer diagnosis in biopsynaïve men with suspected prostate cancer based on elevated prostate-specific antigen values: results from a randomized prospective blinded controlled trial. European Urology 2016;69(3):419-25.

Tsivian 2017 {published and unpublished data}. Tsivian M, Gupta RT, Tsivian E, Qi P, Mendez MH, Abern MR, et al. Assessing clinically significant prostate cancer: diagnostic properties of multiparametric magnetic resonance imaging compared to three-dimensional transperineal template mapping histopathology. International Journal of Urology 2017;24(2):137-43.

Van der Leest 2018 {published data only}. Van der Leest MM, Cornel EB, Israël B, Hendriks RJ, Padhani AR, Hoogenboom M, et al. Head-to-head comparison of transrectal ultrasound-guided prostate biopsy versus multiparametric prostate resonance imaging with subsequent magnetic resonance-guided biopsy in biopsy-naïve men with elevated prostate-specific antigen: a large prospective multicentre clinical study. European Urology 23 November 2018 [Epub ahead of print];S0302-2838(18):30880-7. [DOI: 10.1016/j.eururo.2018.11.023]

5.2 EvT 5.14

Zitat	Population	Suchstrategie	eingeschlossene Studien	Heterogenität	Ergebnisse	methodische Validität	LoE
Wegelin O. Comparing Three Different Techniques for Magnetic Resonance Imaging-targeted Prostate Biopsies: A Systematic Review of In-bore versus Magnetic Resonance Imaging-transrectal Ultrasound fusion versus Cognitive Registration. Is There a Preferred Technique? Eur Urol 2016.	primary diagnostic studies reporting on PCa detection rates among pat.s at risk of PCa using MRI-TB, or FUS-TB, or COG-TB n = 43 articles relevant for review question n = 25 studies reporting on both MRI-GB (any technique) and TRUS-GB results separately within same population inclusion of publications up to Oct.2014	A comprehensive search of literature (PubMed, Embase, and CENTRAL databases; range of last 10y) was performed. The search terms used were ‘‘Prostate OR Prostatic Neoplasm’’ AND ‘‘Biopsy’’ AND ‘‘Magnetic Resonance Imaging OR Image-Guided Biopsy’’	Published primary diagnostic studies reporting on PCa detection rates among patients at risk of PCa using MRI-TB, or FUS-TB, or COG-TB were included.	Heterogenität: The 43 included studies demonstrate significant variation in cohort size, ranging from 16 to 1003 (median, 106) patients. The mean PSA value ranged from 5.1 ng/ml to 15.3 ng/ml and the mean age ranged from 61.8 yr to 70.0 yr. The populations varied with respect to biopsy history. For all subsequent analysis, we used clinical homogenous data on detection rates among patients with no or negative prior biopsies. Considerable heterogeneity was found with respect to the applied definition of csPCa. Furthermore, several studies did not present a definition of csPCa, and consequently did not report data on the detection of csPCa.	PCa-suspekte MRI-Befunde in 73% der Pat.; Studien (n=6) mit Bx-naiven in 68%, mit vorheriger neg.Bx (n=7 Studien) in 79% Werte für Studien mit Bx-naiv sowie prev.neg.bx gepoolt: MRI-GB and TRUS-GB did not significantly differ in overall PCa detection, rel. sensitivity of 0.98 (95% CI: 0.90-1.07) - SE for MRI-GB: 0.81 ( 0.76-0.85) - SE for TRUS-GB: 0.83 (0.77–0.88) --> MRI-GB missed 19% of all cancers, while TRUS-GB missed 17%. MRI-GB detected significantly more csPCa than TRUS-GB, rel. sensitivity of 1.16 (1.02-1.32) - SE for MRI-GB: 0.90 (0.85-0.94) - SE for TRUS-GB: 0.79 (0.68-0.87) --> MRI-GB missed 10% significant cancers whilst TRUS-GB missed 21% no significant advantage of usage of any one technique of MRI-GB (cognitive / fusion / in-bore) for the detection of csPCa	1. a priori Design - nein 2. Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3. Literaturrecherche min 2 Datenbanken + 1 Zusatz - ja 4. graue Literatur eingeschl. - nein 5. Vollständige Liste ein- und ausgeschl. Studien - nein 6. Details der eingeschlossenen Studien - ja 7. Qualität der eingeschlossenen Studien bewertet - ja 8. In Conclusion Hinweise auf methodische Qualität - ja 9. Heterogenität erhoben?- ? 10. Publication bias (funnel plot) - nein 11. CoI / funding für Review UND für alle Studien berichtet - nein AMSTAR-Score 5-6/11	2+ Aussagen zu MRI-tbx vs. Sbx keine Metaanalyse für Bx-naive Subgruppe (Daten könnten ggf. extrahiert werden)

Zitat	Charakteristika	Ergebnisse	Methodische Bewertung AMSTAR	LoE
Gayet M. The value of magnetic resonance imaging and ultrasonography (MRI/US)-fusion biopsy platforms in prostate cancer detection: a systematic review. BJU Int 2016;117(3):392-400.	systematic review of prospective non-randomised controlled trials or in-patient control studies Suchzeitraum: 01/2004-02/2015 (Begründung: Zulassung von fusion-Plattformen 2004) Population: Bx-naive und Pat. mit vorheriger negativer Bx mit Verdacht auf PCa Vergleichsgruppen: standard Bx (überwiegend 10-12 Stanzen) or another way of MRI-guided TB Endpunkte: (clinically significant) prostate CDRs per patient body of evidence: 11 eingeschl. Studien, 2602 eingeschl. Pat. (min 20, max 1003)	Ergebnisse: CDRs für alle PCa zwischen 35,7-79,5% bei fusion Bx vs. 28,5-56,6% bei Standard-Bx. CDRs für klinisch signifikante PCa zwischen 17,2-47,9% bei fusion Bx vs. 12,2-38% bei Standard-Bx. Sicherheit: nicht erhoben / berichtet author's conclusion: No clear advantage of MRI/US fusion-guided TBs was seen for cancer detection rates (CDRs) of all prostate cancers. However, MRI/US fusion-guided TBs tended to give higher CDRs for clinically significant prostate cancers in our analysis. Important limitations of the present systematic review include: the limited number of included studies, lack of a general definition of ‘clinically significant’ prostate cancer, the heterogeneous study population, and a reference test with low sensitivity and specificity. Although MRI/US-fusion TB has proved its value in men with prior negative biopsies, general use of this technique in diagnosing prostate cancer should only be performed after critical consideration. Before bringing MRI/US fusion-guided TB in to general practice, there is a need for more prospective studies on prostate cancer diagnosis.	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - nein 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - (ja) 4 Bericht über Ausschlüsse - ja 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - ja 9 Heterogenität erhoben?- ja 10 Publication bias berichtet (funnel plot/verbal) - nein 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 7/11	2+
Wu J. Is magnetic resonance/ultrasound fusion prostate biopsy better than systematic prostate biopsy? An updated meta- and trial sequential analysis. Oncotarget 2015;6(41):43571-80.	Metaanalyse mit 16 paired cohort studies (in-patient control) Suchzeitraum: bis Mai 2015 Population: Pat. mit Verdacht auf PCa; keine Unterscheidung, ob Bx-naiv oder nicht Interventionen: MRI-TRUS fusion Bx Vergleichsgruppen: standard biopsy (überwiegend (10-)12 core Bx) Endpunkte: Detektion von PCa body of evidence: 16 eingeschl. Studien, 3105 eingeschl. Pat. (30-1003, jedoch überwiegend kleine Studien)	Heterogenität: moderat (I^2 = 28%) Ergebnisse/Effektivität: es wurden signifikant mehr PCa detektiert mit MRI-US fusion: risk ratio 1,06 (95% KI 1.01-1,12; p=0,03) Subgruppenanalysen: bei moderatem/hohem Verdacht im MRI lag das risk ratio bei 1,46 (95% KI 1.28-1,67; p<0,001; I^2 = 0). bessere Ergebnisse auch bezogen auf klin. signif. PCa: RR 1,19 (95% KI 1.10-1,29; p<0,01; I^2 = 0) Sicherheit: nicht berichtet Qualität der Evidenz für einzelne Outcomes: s. I^2-Werte; geringer Publikationsbias author's conclusion: We found that, although more evidence is needed, MR/US fusion prostate biopsy alone detected more prostate cancers than systematic biopsy and was better than systematic biopsy in detecting clinically significant prostate cancers. For those men with moderate/high suspicion in mp-MRI, MR/US fusion biopsy showed a great advantage.	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - nein 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - ?(3 DB) 4 Bericht über Ausschlüsse - ja 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - nein 9 Heterogenität erhoben?- ja 10 Publication bias berichtet (funnel plot/verbal) - ja 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 6-7/11	2+
Valerio M. Detection of Clinically Significant Prostate Cancer Using Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy: A Systematic Review. Eur Urol 2015;68(1):8-19.	Systematic review mit v.a. paired cohort studies (in-patient control) Suchzeitraum: bis Dez. 2013 body of evidence: 15 eingeschl. Studien (davon 14 paired cohort design) (+ Bericht über 7 weitere nicht-publ.), 2293 eingeschl. Pat. (13-582) Population: Pat. in 3 Studien Bx-naiv, in 3 Studien vorherige negative TRUS-Bx, in 8 Studien gemischt Interventionen: MRI-TRUS fusion Bx Vergleichsgruppen: current standard of TRUS biopsy (10-12 Stanzen) (no adequate reference test in any of the studies) Endpunkte: Detektionsrate klin. signif. PCa (jeweils definiert in Studien, z.T. unterschiedlich)	Ergebnisse Effektivität: The median detection of clinically significant disease was 23,6% (range 4,8-52%) for standard biopsy and 33,3% (13,2-50%) for MRI-TRUS fusion. Across all studies in which both rates were reported, fusion Bx allowed the detection of greater numbers of clinically significant cancers compared to standard Bx. The absolute difference in detection rates was a median of 6,8% (0,9-41,4%) always in favour of fusion Bx. Considering absolute differences, fusion Bx detected a median of 9,1% (5-16,2%) additional clinically significant cancers that were missed by standard Bx alone. Detektion PCa insgesamt (signifikant / insignifikant): ähnliche Werte (allerdings in 4 Studien höhere Detektionsraten mit Standard-TRUS) Efficiency: The median difference in number of cores needed to detect one man with clinically significant cancer was 32,1 cores in favour of the targeted approach. Sicherheit: AEs nur in 2 Studien berichtet, davon in 1 nicht vorgekommen, in der anderen nicht zu unterscheiden, welches Verfahren zu AE geführt hat. Heterogenität der eingeschl. Populationen vorhanden (wird als positiv diskutiert: Erhöhung der externen Validität) Qualität der Evidenz für einzelne Outcomes: most studies had low RoB and low applicability concerns with respect to pat. selection. In four studies the index test domain demonstrated a high RoB and applicability concern. Limitations: 1) the definition of clinically significant disease varied between studies.2) it was not possible to determine the overall accuracy of a MRI-TRUS image fusion approach because an accurate reference test was not used. author's conclusion: mpMRI-US fusion targeted Bx detect more clinically significant cancers using fewer cores compared with standard Bx. [findings need to be confirmed by large multicentre validating studies]	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - ja 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - ja 4 Bericht über Ausschlüsse - ja 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - ja 9 Heterogenität erhoben?- nein 10 Publication bias berichtet (funnel plot/verbal) - nein 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 7/11	2+
Schoots IG. Magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol 2015;68(3):438-50.	Metaanalyse von ausschl. Studien mit beiden Interventionen / Methoden beim selben Pat. (in-patient-control studies) Suchzeitraum: bis Mai 2014 Population: Pat. mit positivem MRI (keine Einschränkungen bzgl. Alter) Interventionen: MRI-targeted biopsy und TRUS-Bx (8-12 Stanzen), jeweils im selben Pat. Vergleichsgruppen: jeweils der selbe Pat. mit MRI-TBx und (davon unabh.) TRUS-Bx (überwiegend 10-12 Stanzen) Endpunkte: detection of PCa (significant, insignificant - hier jedoch unterschiedl. Definitionen in den Studien) by MRI-TBx vs. TRUS-Bx body of evidence: 16 eingeschl. Studien, 1926 eingeschl. Pat. (Studien: 7x MRI-visual / 10x -fusion / 1x -in-bore)	Heterogenität untersucht bzgl. patient recruitment (initial Bx / prev.neg. / mixed); navigational system (MRI-visual / -fusion / -in-bore), jeweils bezogen aufeinander. Heterogenität (I^2 >40%) in den meisten Analysen vorhanden Ergebnisse: keine signifikanten Unterschiede zwischen MRI-TBx und TRUS-Bx bzgl. overall PCa-Detektion (Sensitivität: 0,85; 95%-KI: 0,80-0,89 bzw. 0,81 und 0,70-0,88) MRI-TBx and TRUS-Bx did not significantly differ in overall prostate cancer detection, with a relative sensitivity of 1.05 (95% CI 0.94–1.19) MRI-TBx and TRUS-Bx missed the diagnosis of prostate cancer in 15% and 19% of cases, respectively, with a concordance between the tests of 65% (54–74%). relevante Subgruppenanalysen: relative Sensitivität von MRI-fusion/TRUS =1,09, d.h. höhere Detektion durch MRI-fusion, jedoch hohe Heterogenität (I^2 89) bzgl. signifikantem PCa: relative Sensitivität MRI-fusion /TRUS=1,29 Subgruppe Pat. mit vorhergehender negativer Biopsie: relative Sensitivität 1,54 (vs. 1,10 bei initialer Biopsie) author's conclusion: In men with clinical suspicion of prostate cancer and a suspicious lesion seen on multiparametric MRI, MRI-TBx and TRUS-Bx did not differ in overall detection of prostate cancer. However, MRI-TBx had a higher rate of detection of potentially significant prostate cancer and a lower rate of detection of insignificant prostate cancer compared to the standard TRUS-Bx. Subgroup analysis showed that MRI-TBx improved the detection of significant prostate cancer in men with a previous negative biopsy, rather than in men with an initial biopsy. However, we found significant heterogeneity, which limits the strengths of the conclusions that can be made. Furthermore, as a consequence of underlying methodological flaws of MRI-TBx, the comparison to standard systematic biopsy needs to be regarded with caution.	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - nein 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - ja 4 Bericht über Ausschlüsse - ? (We excluded unpublished data or abstracts because information that is needed to correctly assess the study quality and interpret the results was not available in abstracts.) 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - ja 9 Heterogenität erhoben?- ja 10 Publication bias berichtet (funnel plot/verbal) - ja 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 7/11	2+

5.2.1 EvT 5.15

Zitat	Charakteristika	Ergebnisse	Methodische Bewertung AMSTAR	LoE
Schoots IG. Magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol 2015;68(3):438-50.	Metaanalyse von ausschl. Studien mit beiden Interventionen / Methoden beim selben Pat. (in-patient-control studies) Suchzeitraum: bis Mai 2014 Population: Pat. mit positivem MRI (keine Einschränkungen bzgl. Alter) Interventionen: MRI-targeted biopsy und TRUS-Bx (8-12 Stanzen), jeweils im selben Pat. Vergleichsgruppen: jeweils derselbe Pat. mit MRI-TBx und (davon unabh.) TRUS-Bx (überwiegend 10-12 Stanzen) Endpunkte: detection of PCa (significant, insignificant - hier jedoch unterschiedl. Definitionen in den Studien) by MRI-TBx vs. TRUS-Bx body of evidence: 16 eingeschl. Studien, 1926 eingeschl. Pat. (Studien: 7x MRI-visual / 10x -fusion / 1x -in-bore)	Heterogenität untersucht bzgl. patient recruitment (initial Bx / prev.neg. / mixed); navigational system (MRI-visual / -fusion / -inbore), jeweils bezogen aufeinander. Heterogenität (I^2 >40%) in den meisten Analysen vorhanden Ergebnisse: keine signifikanten Unterschiede zwischen MRI-TBx und TRUS-Bx bzgl. overall PCa-Detektion (Sensitivität: 0,85; 95%-KI: 0,80-0,89 bzw. 0,81 und 0,70-0,88) MRI-TBx and TRUS-Bx did not significantly differ in overall prostate cancer detection, with a relative sensitivity of 1.05 (95% CI 0.94–1.19) MRI-TBx and TRUS-Bx missed the diagnosis of prostate cancer in 15% and 19% of cases, respectively, with a concordance between the tests of 65% (54–74%). relevante Subgruppenanalysen: relative Sensitivität von MRI-fusion/TRUS =1,09, d.h. höhere Detektion durch MRI-fusion, jedoch hohe Heterogenität (I^2 89) bzgl. signifikantem PCa: relative Sensitivität MRI-fusion /TRUS=1,29 Subgruppe Pat. mit vorhergehender negativer Biopsie: relative Sensitivität 1,54 (vs. 1,10 bei initialer Biopsie) author's conclusion: In men with clinical suspicion of prostate cancer and a suspicious lesion seen on multiparametric MRI, MRI-TBx and TRUS-Bx did not differ in overall detection of prostate cancer. However, MRI-TBx had a higher rate of detection of potentially significant prostate cancer and a lower rate of detection of insignificant prostate cancer compared to the standard TRUS-Bx. Subgroup analysis showed that MRI-TBx improved the detection of significant prostate cancer in men with a previous negative biopsy, rather than in men with an initial biopsy. However, we found significant heterogeneity, which limits the strengths of the conclusions that can be made. Furthermore, as a consequence of underlying methodological flaws of MRI-TBx, the comparison to standard systematic biopsy needs to be regarded with caution.	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - nein 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - ja 4 Bericht über Ausschlüsse - ? (We excluded unpublished data or abstracts because information that is needed to correctly assess the study quality and interpret the results was not available in abstracts.) 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - ja 9 Heterogenität erhoben?- ja 10 Publication bias berichtet (funnel plot/verbal) - ja 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 7/11	2+

Artikel (Autor, Jahr)/ Studientyp	Anzahl der Patienten/ Patientenmerkmale	Intervention/ ggf. Nachverfolgung	Vergleichsintervention Referenzstandard	Outcomes	Ergebnisse	Bemerkungen	Evidenzniveau SIGN
Thema: funktionelles MRT nach negativer Biopsie
Cheikh A.B. et al, 2009 [101] retrospektive unizentrische Fallserie Lyon Angabe zu Interessenkonflikten: k.A.	n= 93 Patienten aus einer Institution mit mind. 1x negativer Biopsie, im Mittel 1,9 (1-5), im Mittel 12,6 Stanzen pro Biopsiesitzung mittl. Alter 63,2J (52-74) 93,5% PSA-Wert >4ng/ml, mittl. Wert 9,63ng/ml (1,6-40) 22,6% auffällige DRU Mittl. P.-vilumen 49,8	MRT T2-gew. + DCE-MRT mit späterer systematischer TRUS-gesteuerter Biopsie (im Mittel nach 26 Tagen) , 12 Stanzen und suspekte Bezirke vom MRT 1,5 T „pelvic phased array coil“, T1+T2 gewichtete Auswertung, suspekt: alle noduläre Strukturen niedriger Intensität bei T2 + alle mit früher Anreicherung in der peripheren Zone und der Samenblasenwand Erfahrung der radiologischen Untersucher: 2x2, 5 und 15J	Keine, getrennte Auswertung für T2-gewichtete Befunde und DCE-MRT Referenzstandard: Histologie aus Biopsie	Sensitivität Spezifität PPW NPW	Im Mittel Entnahme von 15,8+/-1,9 Stanzen (12-21) Nachweis von PCa in 24,7% der Patienten, 86% in der peripheren Zone (bei 25,6% nach 1 vorausgegangener Biopsie, 25% nach 2. Biopsie, 22,2% nach 3 Biopsie) 1. Sensitivität T2w-MRT: 47,8% [95%KI 26,8-69,4] DCE-MRT: 82,6% [95%KI 61,2-95%] T2w oder DCE suspekt: 82,6% [61,2-95%] 2. Spezifität T2w-MRT: 44,3% [95%Ki 32,4-56,7] DCE-MRT: 20% [95%KI 11,4-31,3] T2w oder DCE suspekt: 15,7[8,2-26,4] 3. PPW T2w-MRT: 20,4%[95%KI 10,6-35,5] DCE-MRT: 24,4% [95%KI 15,3-35,4] T2w oder DCE suspekt: 23,2%[14,6-33,8] 4. NPW T2w-MRT: 79,5% [63,5-90,7] DCE-MRT: 93,3% [68,1-99,8] T2w oder DCE suspekt: 100 [71,5-100]	Autoren geben an, dass Untersuchungen nach strikt standardisiertem Vorgehen erfolgten. MRT wurde jeweils von dem Radiologen ausgewertet, der auch die erneute TRUS gesteuerte Biopsie vornahm. MRT gesteuerte Re-Biopsie wird als zeitaufwändig und teuer, in der täglichen Routine nicht machbar gewertet Unterscheidung nach Gleason Score (<7, =7) zeigte keine sign. Ergebnisse	3
Labanaris AP et al, 2010 prospektive unizentrische Fallserie Nürnberg Interessenkonflikte: k.A.	N=260 konsekutive Patienten (2004-2008) Mittl. Alter PSA-Wert > 4ng/ml, auffällige DRU, mind. 1x vorausgegangene negative Biopsie Ausschlussgründe: >75J, Herzschritt-macher, Z.n. pelviner Chirurgie, chron. Entz. Damerkrankung, externer Strahlentherapie, analstriktur oder hochgradige Hämorrhoiden	MRT mit endorektal Spule + diff.gew. MRT+DCE-MRT und TRUS gesteuerte 18 Core Biopsie + 3 Stanzen pro suspekter Zone 1.0 T T1- und T2 gewichtete Sequenzen Auswertung durch erfahrene verblindete Radiologen Suspekt: T1-Wic htung: Assymmetrie, irreguläre Begreunzung, Verlust des neurovaskulären Bündels T2: verminderte Signalintensität, Obliteration des retroprostatischen Winkels, + wie T1	Referenz standard: Histologie aus Biopsie	Sensitivität, Spezifität,	55% mit PCa (143/260) Durch gezielte Biopsien entdeckte Karzinome: 67% (96/143) Sensitivität : MRT gezielte Biopsie: 84,9%(96/113) nur systematische Biopsie: 32,86% (47/143) Spezifität: MRT gezielte Biospie: 49,65% (49,65%) Nur systematische Biopsie: n.a.	Absolute Zahlen aus %-Zahlen errechnet, da n.a. Aus jeder auffälligen Region 3 gezielte Biopsien + 18 Biopsien systematisch : insgesamt hohe Anzahl an Biopsien	2-3
Sciarra A. et al, 2010 RCT, uni-zentrisch, Rom Angaben zu Interessenkonflikten: keine	n=215 konsekutive Patienten 1/07-1/09 eingeschlossen n=180 (83,7%) mittl. Alter 63,5J (49-74J) negative systematische Biopsie (alle in diesem Zentrum durchgeführt) PSA 4-10ng/ml DRU o.B. Ausschlussgründe: Vorherige hormonelle, radiologische oder chirurgische Therapie oder keine MR+MRS-DCE-MRT möglich	n=90 2. Biopsie systematische + gezielt e Biopsien aufgrund des MRT+MRS+DCE-MRT (T2-gewichteten) Befunds innerhalb von 60 Tagen N= 45 mit Auffälligkeiten N=45 ohne Technik MRT : 1,5Tesla endorektale Spule T2-Wichtung in axialer, sagittaler und coronaler Ebene MRS cut-off bei (choline+creatine)/ citrate ratio >0,8 wenn in peripherer Zone, als Artefakt klassifiziert bei gleichzeitig T1-gewichteter hoher Intensität	n=90 2. Biopsie, systematisch, TRUS-geleitet innerhalb von 60 Tagen Falls negativ: 50/68 mit anschließender MRT/MRS/DCE-MRT und 3. Biopsie ggf. plus gezielte Biopsien (n=30) Referenz-standard: Histologie aus Biopsie	Sensitivität Spezifität Positiver prädiktiver Wert Negativer prädiktiver Wert ROC-Kurven	Patientencharakteristika für beide Gruppen im Hinblick auf mittl. Alter, PSA-Wert und Prostatavolumen gleich Anteil Karzinome 2.Biopsie systematische Biopsie: 24,4% (22/90) systematische Biopsie + MRT: 48.8% (44/90) Sensitivität 2. Biopsie systematisch (aus Ergebnissen 3. Biopsie): 45,8% 2. Biopsie MRT+MRS+DCE-MRT: 93,2% (41/44) Spezifität 2. Biopsie systematisch: 100% 2. Biopsie MRT+MRS+DCE-MRT: 91,3% Positiver prädiktiver Wert 2. Biopsie: 100% 2. Biopsie MRT+MRS+DCE-MRT: 91,1% (41/45) Negativer prädiktiver Wert 2. Biopsie systematisch (aus Ergebnissen 3. Biopsie): 66,6% 2. Biopsie MRT+MRS+DCE-MRT: 93,3% (42/45) Accuracy: 2. Biopsie systematisch n.a. 2. Biopsie MRT+MRS+DCE-MRT: 90,7% Mehrwert zusätzliches DCE-MRT: n=3 Karzinomdiagnosen Multivariate Analyse zeigen auffällige MRT-Techniken als einzigen signifikanten Parameter für das Vorliegen von PCa (nicht Alter, Volumen, PSA)	Keine Angaben zur Randomisierungsstrategie Testgüteparameter für 3. Biopsie nach komb. MRT-Techniken n.a. Testgüteparameter aus Angaben in der Studie berechnet, da dort %-Angaben nicht nachvollziehbar Keine Konfidenzintervalle, Power? Klinische Signifikanz der entdeckten Karzinome?	1+

Artikel
(Autor, Jahr)/
Studientyp

Anzahl der Patienten/
Patientenmerkmale

Intervention/
ggf. Nachverfolgung

Vergleichsintervention
Referenzstandard

Outcomes

Ergebnisse

Bemerkungen

Evidenzniveau

SIGN

Thema: funktionelles MRT nach negativer Biopsie

Cheikh A.B. et al, 2009 [101]
retrospektive unizentrische Fallserie
Lyon

Angabe zu Interessenkonflikten:
k.A.

n= 93

Patienten aus einer Institution mit mind. 1x negativer Biopsie, im Mittel 1,9 (1-5), im Mittel 12,6 Stanzen pro Biopsiesitzung

mittl. Alter 63,2J (52-74)

93,5% PSA-Wert >4ng/ml, mittl. Wert 9,63ng/ml (1,6-40)
22,6% auffällige DRU

Mittl. P.-vilumen 49,8

MRT T2-gew. + DCE-MRT mit späterer systematischer TRUS-gesteuerter Biopsie (im Mittel nach 26 Tagen) , 12 Stanzen und suspekte Bezirke vom MRT
1,5 T „pelvic phased array coil“, T1+T2 gewichtete Auswertung, suspekt: alle noduläre Strukturen niedriger Intensität bei T2 + alle mit früher Anreicherung in der peripheren Zone und der Samenblasenwand

Erfahrung der radiologischen Untersucher: 2x2, 5 und 15J

Keine, getrennte Auswertung für T2-gewichtete Befunde und DCE-MRT

Referenzstandard:
Histologie aus Biopsie

Sensitivität

Spezifität

PPW

NPW

Im Mittel Entnahme von 15,8+/-1,9 Stanzen (12-21)

Nachweis von PCa in 24,7% der Patienten, 86% in der peripheren Zone (bei 25,6% nach 1 vorausgegangener Biopsie, 25% nach 2. Biopsie, 22,2% nach 3 Biopsie)

1. Sensitivität
T2w-MRT: 47,8% [95%KI 26,8-69,4]

DCE-MRT: 82,6% [95%KI 61,2-95%]

T2w oder DCE suspekt: 82,6% [61,2-95%]

2. Spezifität
T2w-MRT: 44,3% [95%Ki 32,4-56,7]

DCE-MRT: 20% [95%KI 11,4-31,3]
T2w oder DCE suspekt: 15,7[8,2-26,4]

3. PPW
T2w-MRT: 20,4%[95%KI 10,6-35,5]

DCE-MRT: 24,4% [95%KI 15,3-35,4]
T2w oder DCE suspekt: 23,2%[14,6-33,8]

4. NPW
T2w-MRT: 79,5% [63,5-90,7]

DCE-MRT: 93,3% [68,1-99,8]
T2w oder DCE suspekt: 100 [71,5-100]

Autoren geben an, dass Untersuchungen nach strikt standardisiertem Vorgehen erfolgten.
MRT wurde jeweils von dem Radiologen ausgewertet, der auch die erneute TRUS gesteuerte Biopsie vornahm.

MRT gesteuerte Re-Biopsie wird als zeitaufwändig und teuer, in der täglichen Routine nicht machbar gewertet

Unterscheidung nach Gleason Score (<7, =7) zeigte keine sign. Ergebnisse

Labanaris AP et al, 2010 prospektive unizentrische Fallserie
Nürnberg

Interessenkonflikte: k.A.

N=260 konsekutive Patienten (2004-2008)

Mittl. Alter

PSA-Wert > 4ng/ml, auffällige DRU,

mind. 1x vorausgegangene negative Biopsie

Ausschlussgründe: >75J, Herzschritt-macher, Z.n. pelviner Chirurgie, chron. Entz. Damerkrankung, externer Strahlentherapie, analstriktur oder hochgradige Hämorrhoiden

MRT mit endorektal Spule + diff.gew. MRT+DCE-MRT und TRUS gesteuerte 18 Core Biopsie + 3 Stanzen pro suspekter Zone

1.0 T T1- und T2 gewichtete Sequenzen

Auswertung durch erfahrene verblindete Radiologen

Suspekt: T1-Wic htung: Assymmetrie, irreguläre Begreunzung, Verlust des neurovaskulären Bündels

T2: verminderte Signalintensität, Obliteration des retroprostatischen Winkels, + wie T1

Referenz
standard:
Histologie aus Biopsie

Sensitivität, Spezifität,

55% mit PCa (143/260)

Durch gezielte Biopsien entdeckte Karzinome: 67% (96/143)

Sensitivität :

MRT gezielte Biopsie: 84,9%(96/113)
nur systematische Biopsie: 32,86% (47/143)

Spezifität:

MRT gezielte Biospie: 49,65% (49,65%)

Nur systematische Biopsie: n.a.

Absolute Zahlen aus %-Zahlen errechnet, da n.a.

Aus jeder auffälligen Region 3 gezielte Biopsien +

18 Biopsien systematisch : insgesamt hohe Anzahl an Biopsien

2-3

Sciarra A. et al, 2010

RCT, uni-zentrisch, Rom

Angaben zu Interessenkonflikten: keine

n=215 konsekutive Patienten 1/07-1/09
eingeschlossen n=180 (83,7%)

mittl. Alter 63,5J (49-74J)

negative systematische Biopsie (alle in diesem Zentrum durchgeführt)

PSA 4-10ng/ml DRU o.B.

Ausschlussgründe:

Vorherige hormonelle, radiologische oder chirurgische Therapie oder keine MR+MRS-DCE-MRT möglich

n=90

2. Biopsie systematische + gezielt e Biopsien aufgrund des MRT+MRS+DCE-MRT (T2-gewichteten) Befunds innerhalb von 60 Tagen

N= 45 mit Auffälligkeiten

N=45 ohne

Technik MRT : 1,5Tesla endorektale Spule

T2-Wichtung in axialer, sagittaler und coronaler Ebene

MRS cut-off bei (choline+creatine)/

citrate ratio >0,8 wenn in peripherer Zone, als Artefakt klassifiziert bei gleichzeitig T1-gewichteter hoher Intensität

n=90

2. Biopsie, systematisch, TRUS-geleitet innerhalb von 60 Tagen

Falls negativ:

50/68 mit anschließender

MRT/MRS/DCE-MRT und 3. Biopsie ggf. plus gezielte Biopsien (n=30)

Referenz-standard:
Histologie aus Biopsie

Sensitivität
Spezifität

Positiver prädiktiver Wert
Negativer prädiktiver Wert

ROC-Kurven

Patientencharakteristika für beide Gruppen im Hinblick auf mittl. Alter, PSA-Wert und Prostatavolumen gleich
Anteil Karzinome 2.Biopsie
systematische Biopsie: 24,4% (22/90)
systematische Biopsie + MRT: 48.8% (44/90)

Sensitivität
2. Biopsie systematisch (aus Ergebnissen 3. Biopsie): 45,8%
2. Biopsie MRT+MRS+DCE-MRT: 93,2% (41/44)

Spezifität
2. Biopsie systematisch: 100%
2. Biopsie MRT+MRS+DCE-MRT: 91,3%

Positiver prädiktiver Wert
2. Biopsie: 100%
2. Biopsie MRT+MRS+DCE-MRT: 91,1% (41/45)

Negativer prädiktiver Wert
2. Biopsie systematisch (aus Ergebnissen 3. Biopsie): 66,6%
2. Biopsie MRT+MRS+DCE-MRT: 93,3% (42/45)

Accuracy:

2. Biopsie systematisch n.a.

2. Biopsie MRT+MRS+DCE-MRT: 90,7%

Mehrwert zusätzliches DCE-MRT: n=3 Karzinomdiagnosen

Multivariate Analyse zeigen auffällige MRT-Techniken als einzigen signifikanten Parameter für das Vorliegen von PCa (nicht Alter, Volumen, PSA)

Keine Angaben zur Randomisierungsstrategie
Testgüteparameter für 3. Biopsie nach komb. MRT-Techniken n.a.

Testgüteparameter aus Angaben in der Studie berechnet, da dort %-Angaben nicht nachvollziehbar

Keine Konfidenzintervalle, Power?

Klinische Signifikanz der entdeckten Karzinome?

Autoren, Jahr,
Studientyp

Untersuchte Studien/
Materialien

Welche Behandlungen wurden geprüft

Charakteristik eingeschlossener Studien /
Befunde in Bezug auf Therapiewirkungen

Literaturbelege

Evidenzniveau (SIGN)

Seitz M. et al, 2009

Systematischer Review

Angabe zu Interessenkonflikten : keine

Systematische Suche in Pubmed (Medline), Embase und der Cochrane Library bis Oktober 2008 alle Sprachen

Keine Angaben zu Suchstrategien, Trefferzahlen, Einschluss-kriterien Autorenanfrage am 31.3. – Antwort am 3.4.: Material nicht verfügbar

Funktionelle MRT-Bildgebung zur Diagnose des Prostatakarzinoms (MRT +MRS, dynamisches kontrastverstärktes MRT, diffusiongewichtetes MRT)

Studienqualität :
Angaben nur in der Schlussfolgerung : « a limited number of small studies », sonst keine Angaben

Ergebnisse :

In der Ergebnisdarstellung eher narrativer Review, im Folgenden v.a. zusammenfassende Darstellung der Ergebnisse.

1. Verbesserte MRT- Qualität durch : « fast spin echo, endorectal coil, multiple imaging planes »

2. Accuracy des MRT für Nachweis von kapselüberschreitendem Wachstum : 54%-83%
3. Accuracy des MRT für Nachweis von Samenblasenbefall : 81-93%

4. Testgüte MRT zum Nachweis Prostatakarzinom
Sensitivität : 41,2%-100%

Spezifität : 50-97%

Positiver prädiktiver Wert : 35,8%-77,8%

Negativer prädiktiver Wert : 63%-100%

Accuracy : 64-75,9%

5. Testgüte funktionelles MRT zum Nachweis Prostatakarzinom und zum Staging

5a. MRT+MRS

Sensitivität :
Diagnose : 63% komb. 67%/76% einzeln (nur Biopsie : 50%)
Staging : 42-93%

Spezifität :
Diagnose : 75% komb. 69%/57% einzeln (nur Biopise : 82%)
Staging : 81-89,3%

Positiver prädiktiver Wert :
Diagnose :89-92%
Staging : 81-83%
Negativer prädiktiver Wert :
Diagnose : 74-82%
Staging : 50-86%
Accuracy :

74,2%, (Reinsberg et al) 79% (Manenti et al.)

Größter Mehrwert für Lokalisationen an Apex (Wefer et al.)

5b. Diffusionsgewichtete MRT

I. Shimofusa et al.
retrospektiv, unizentrisch, konsekutiv, 124 Pat. V.a. PCa,, mittl. PSA-Wert 21,8ng/ml
Ergebnisse : Sensitivität : 86%, Sepzifität 84%, PPW : 90%, NPW : 79%

II. DeSouza NM et al.

Prospektiv, unizentrisch, 33 Pat, PSA-Werte n.a.
Ergebnisse : Sensitivität : 86,7%, Spezifität : 72,2% für Diagnose PCa in P-Zone, ADC (apparent diffusion coefficient)-Werte bei Malignität sign. geringer

III. Morgan VA et al.
prospektiv, unizentrisch, 56 Pat. PSA-Werte 2,3-46ng/ml , erfahrener Beurteiler
Ergebnisse : MRT diff.-gew. (vs MRT) Sensitivität : 73,2% (vs 50%), Spezifität : 80,8% (vs 79,6%), PPW : 74,8% (vs 65,7%), NPW : 79,5% (vs 67m1%), Accuracy 77,5% (vs 66,6%)
IV. Yoshimitsu K et al.
Referenzstandard Prostatektomie-Präparat, sonst k.A.
Ergebnisse : MRT diff. gew. vs. MRT sign. verbesserte PCa-Entdeckungsrate in T-Zone. Korrelation von Gleason Score und ADC
V. Van AS N
Als einzige Studie Referenzstandard « whole-mount, step-section pathology » sonst k.A.
Ergebnisse : MRT diff. gew. vs. MRT sign. Unterschied in ADC von PCa und BPH, aber auch signifikante Überlappung, entscheidend vermutlich relative Unterschiede

5c. DCE-MRT
Studien mit Referenzstandard Histologie aus operativem Präparat (Prostatektomie)

Sensitivität:
Diagnose : 69-95% (Jager et al : vs. MRT 57,5%)
Kapselüberschreitung : 82-91% (surface MRI+DCE-MRT, Bloch et al., n=32, verblindet, PCa-Diagnose bekannt)
Spezifität:
Diagnose : 80-96%
Kapselüberschreitung : 95% (MRT+DCE-MRT, Bloch et al.)

Positiver prädiktiver Wert:
Diagnose : n.a.
Kapselüberschreitung : 90-91% (MRT+DCE-MRT,Bloch et al.)
Negativer prädiktiver Wert:
Diagnose : n.a.
Kapselüberschreitung : 91-95% (MRT+DCE-MRT,Bloch et al.)

Accuracy:
Diagnose : 77,5-92% (Jager et al : vs. MRT 72%)
Kapselüberschreitung : n.a.

Understaging 3-9%, Overstaging 3-6% (Bloch et al.)

VEGF (Vascular Endothelial Growth Factor)-Expression und MVG (microvascular densitiy) sign. Höher bei PCa als beiBPH . Positive Korrelation zwischen Anreicherung, VEGF-Expression und MVD (Ren et al.)

5d. Kombination verschiedener MRT-Techniken
I. Tanimoto et al
prospektiv, unizentrisch, konsekutiv, 83 Pat. mit V.a.PCa, keine weiteren Angaben,
T2-gewichtete Auswertung

Ergebnisse : ROC Az MRT : 0,711, ROC Az MRT diff. gew. : 0,905, ROC Az MRT diff.-gew. + DCE-MRT : 0,966
II. Chen et al.
retrospektiv, unizentrisch, 42 Pat. mit erhöhten PSA-Werten, keine weiteren Angaben,

T2-gewichtete Auswertung,

Ergebnisse : ROC Az MRT : 0,848, ROC Az MRT diff. gew. : 0,860, ROC Az MRS : 0,961. ROC Az MRT+ MRT diff.-gew. + MRS : 0,978

Reinsberg et al, Kozlowski et al, Mazaheri et al: « showed similar results …for combined MR protocols », sonst k.A.

6. MRT nach negativer Biopsie

I. Beyersdorff et al.
prospektiv, unizentrisch, sonst k.A.
Ergebnisse : Sensitivität 83% (DRE : 33%, TRUS 33%), PPW 50% (DRE 67%, TRUS : 57%), MRT korrelierte nicht mit individueller Biopsie-Lokalisation.
II. Comet-Battle et al.
92 Pat. mit erhöhtem PSA-Wert (>4ng/ml) und/oder auffälliger DRU mit 1-5 MRT-gesteuerten Biopsie-Serien
Ergebnisse : Accuracy MRT+DRU+PSA 83% vs DRU/PSA allein jeweils 70%. Wahrscheinlichkeit von PCa bei PSA-Wert 5-15ng/ml und negativer DRU/MRT 5-10% bei 1. und 2. Biopsieserie und <3% bei weiteren Biopsieserien. Schlussfolgerung Autoren : nach 2 Biopsieserien ist eine negative MRT zur Vemeidung weiterer Biopsien ausreichend.
III. Yuen et al.
24 Pat. mit mind. 1x negativer TRUS-gesteuerter Biopsie [und erhöhtem PSA-Wert] mit MRT/MRS (10 Zufallsbiopsien und bis zu 4 gezielte Biopsien), PCa entdeckt in 7/24 Pat (29,1%)
Ergebnisse : MRT/MRS komb. Sensitivität 100%, Spezifität 70,6%, PPW : 58,3%, NPV : 100%, in 2/7 Pat nur duch bezielte Biopsien

IV. Amsellem-Ouzana et al.
42 Pat. , im Mittel 2x negative TRUS-gesteuerte Biopsie, mittl.PSA-Wert 12ng/ml (3,9-35) mit MRT/MRS und 10 gezielten Biopsien. PCa entdeckt in 15/42 (35,7%)
Ergebnisse : Sensitivität 73,3%, Sepzifität 96,3%, PPW : 91,6%, NPW : 86,6%, Accuracy : 88%, 9x Tumorlokalisation Biopsie und MRT/MRS identisch, 5x Tumorlokalisation Biopsie und MRS identisch.

V. Lattouf et al.
konsekutiv, unizentrisch, 26 Pat. nach negativer TRUS-gesteuerter Biopsie mit MRT/DCE-MRT, T2-gewichtete Auswertung
Ergebnisse : NPW MRT 14%, NPW DCE-MRT 15%, Unterschiede n.s.

Schlussfolgerung der Autoren des systematischen Reviews :

“MRI appears to be useful for ruling out cancer in patients at risk for PCa with previous negative biopsies; in addition, there is evidence that the use of MRI to plan targeted biopsies may lead to the detection of cancers that would have been missed on systematic biopsies.”

7. MRT zur Charakterisierung des Prostatakarzinoms
I. Zakian et al.
123 Pat. mit MRS vor Prostatektomie.
Ergebnisse : MRT/MRS sensitiver in schlecht differenzierten Tumoren (Gleason Score mind. 7b).
II. Hom et al.
k.A.

Ergebnisse : Tumoren mit Gleason 6, die mit MRT/MRS nicht diagnostiziert wurden, waren signifikant kleiner als die diagnostizierten.
III. DeSouza et al.
MRT diff.-gew., sonst k.A .
Ergebnisse : Diffussion bei low risk PCa signifikant unterschiedlich von Diff. bei intermediate oder high risk PCa
IV. Shukla-Dave et al.
k.A. zu Patienten
Erstellung eines Nomogramms zur Vorhersage eines insignifikanten PCa (<0,5cm³) unter Berücksichtigung von klinischen Parametern, Biospie-Daten und MRT/MRS.
Ergebnisse : Diskriminierung am besten mit Kombination von « Kattan medium nomogram model » (cT1c oder cT2, 1. und 2. Biopsie mit Gleason Score 1-3 (Score =6) ; PSA-Wert vor Behandlung <20ng/ml, >50% Biopsien Ca-positiv) + MRT/MRS : ROC Area under the curve : 0,858, signifikant besser als bestes klinische Modell : 0,726.

1. Engelbrecht MR, Jager GJ, Laheij RJ, et al, Eur Radiol 2002;12:2294–302.

2. Beyersdorff D, Taymoorian K, Knosel T, et al. AJR Am J Roentgenol 2005; 185: 1214–20., Huch Boni RA, Boner JA, Lutolf UM, et al. JComputAssistTomogr 1995;19:23 , Yu KK, Hricak H, Alagappan R et al. ,Radiology 1997;202:697–702. 2–7. Tempany CM, Zhou X, Zerhouni EA, et al. Radiology 1994;192:47–54.,

3. Ikonen S, Karkkainen P, Kivisaari L, et al Eur Radiol 2001;11:236–41., Park BK, Kim B, Kim CK, Lee HM, Kwon GY. J Comput Assist Tomogr 2007;31:534–8

Sala E, Akin O, Moskowitz CS, et al. Radiology 2006;238:929–37.,

4. Casciani E, Polettini E, Bertini L, et al. Abdom Imaging 2007;32: 796–802, Chen M, Dang HD, Wang JY, et al. Acta Radiol 2008;49:602–10. Cirillo S, Petracchini M, Della Monica P, et al. Clin Radiol 2008; 63:871–9., Costouros NG, Coakley FV, Westphalen AC, et al. AJR Am J Roentgenol 2007; 188:812–6. Kubota Y, Kamei S, Nakano M, et al.. Int J Urol 2008;15:322–6, discussion 327., Tamada T, Sone T, Jo Y, et al. Radiology 2008;248: 531–9., Tanimoto A, Nakashima J, Kohno H, Shinmoto H, Kuribayashi S. J Magn Reson Imaging 2007;25:146–52.

5a. Diagnose Sens./Spez komb., PPW, NPW: Scheidler J, Hricak H, Vigneron DB, et al. Radiology 1999; 213:473–80.

Diagnose Sens./Spez. einzeln + Staging Sens./Spez./PPW, NPW: Mueller-Lisse UG, Vigneron DB, Hricak H, et al. Radiology 2001;221:380–90. Jung JA, Coakley FV, Vigneron DB, et al. Radiology 2004;233: 701–8. Swanson MG, Vigneron DB, Tabatabai ZL, et al. Magn Reson Med 2003;50:944–54. Wefer AE, Hricak H, Vigneron DB, et al. J Urol 2000;164:400–4. Futterer JJ, Scheenen TW, Heijmink SW, et al. Invest Radiol 2007; 42:116–22. Accuracy: Wefer AE, Hricak H, Vigneron DB, et al. J Urol 2000; 164:400–4. Manenti G, Squillaci E, CarlaniM,Mancino S, Di RomaM, Simonetti G. Radiol Med (Torino) 2006; 111:22–32. Reinsberg SA, Payne GS, Riches SF, et al. AJR Am J Roentgenol 2007;188:91–8.
5b. Shimofusa R, Fujimoto H, Akamata H, et al. J Comput Assist Tomogr 2005;29: 149–53. DeSouza NM, Reinsberg SA, Scurr ED, Brewster JM, Payne GS. Br J Radiol 2007;80:90–5. Morgan VA, Kyriazi S, Ashley SE, deSouza NM. Acta Radiol 2007;48:695–703. Yoshimitsu K, Kiyoshima K, Irie H, et al. J Magn Reson Imaging 2008;27: 132–9. Van As N, Charles-Edwards E, Jackson A, et al. Br J Radiol 2008;81:456–62

5c. Jager GJ, Ruijter ET, van de Kaa CA, et al. Radiology 1997;203:645–52. Ogura K, Maekawa S, Okubo K, et al Urology 2001 ;57:721–6. Kiessling F, Lichy M, Grobholz R, et al. Eur Radiol 2004;14: 1793–801. Schlemmer HP, Merkle J, Grobholz R, et al. Eur Radiol 2004;14:309–17. Kim JK, Hong SS, Choi YJ, et al. J Magn Reson Imaging 2005;22:639–46. Futterer JJ, Heijmink SW, Scheenen TW, et al. Radiology 2006;241:449–58. Bloch BN, Furman-Haran E, Helbich TH, et al. Radiology 2007;245:176–85. Ren J, Huan Y, Wang H, et al. Clin Radiol 2008;63: 153–9.

5d. Tanimoto A, Nakashima J, Kohno H, Shinmoto H, Kuribayashi S. J Magn Reson Imaging 2007;25:146–52. Chen M, Dang HD, Wang JY, et al. Acta Radiol 2008;49:602–10. Reinsberg SA, Payne GS, Riches SF, et al. AJR Am J Roentgenol 2007; 188:91–8. Kozlowski P, Chang SD, Jones EC, Berean KW, Chen H, Goldenberg SL. J Magn Reson Imaging 2006;24:108–13. Mazaheri Y, Shukla-Dave A, Hricak H, et al. Radiology 2008; 246: 480–8.

6. Beyersdorff D, Taupitz M, Winkelmann B, et al. Radiology 2002;224:701–6. Comet-Batlle J, Vilanova-Busquets JC, Saladie´-Roig JM et al. , Eur Urol 2003;44:201–8, discussion 207–8. Yuen JS, Thng CH, Tan PH, et al J Urol 2004; 171:1482–6. Amsellem-Ouazana D, Younes P, Conquy S, et al., Eur Urol 2005;47:582–6. Lattouf JB, Grubb 3rd RL, Lee SJ, et al BJU Int 2007;99:1041–6.
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2- bis 3

Zitat	Population	Intervention	Studiendesign	Ergebnisse	Methodische Qualität	Bewertung
Delongchamps et al. Are Magnetic Resonance Imaging-Transrectal Ultrasound Guided Targeted Biopsies Noninferior to Transrectal Ultrasound Guided Systematic Biopsies for the Detection of Prostate Cancer? J Urol 2016	108 biopsy naïve pat.s (PSA 4-20ng), normal DRE and a single suspicious image on MRI June- Oct.2014	systematic biopsy by a first operator blinded to MRI, immediately followed by 3 targeted biopsies within the suspicious image by a second operator	prospective cohort study (data from 7 study centres) csPCa definition: max.cancer core length >5mm for GSC 6 or any mccl for GSC 7 or greater (START criteria)	sbx and tbx detected cancer in 66 (61.1%) and 61 patients (56.5%), respectively. The mean difference was -4.5% (95%CI lower bound of -11.8%). Per-protocol analysis (13 pat. excluded): csPCa was detected in 50 (46.2%) and 52 patients (48.1%) with sbx and tbx, respectively (p = 0.69). mean difference of -5.2% (95% CI lower bound of -13.1%). 6/14 missed by tbx but detected by sbx were csPCa 8/9 missed by sbx but detected by tbx were csPCa Tbx seemed to be inferior to sbx for overall PCa detection. Detection of csPCa did not differ between tbx and sbx.	Studientyp - prospective cohort study Patientencharakteristika beschrieben (Tabelle)? - ja ausbalanciert zwischen den Gruppen? - n.a. Drop-out beschrieben/Consort-Diagramm? - ja Statistische Methoden beschrieben? - ja angewendete Methoden und Definitionen beschrieben (z. B. Schmerzskala, Definition von Schmerz, Messmethoden etc.) - ja ITT-Analyse? - ja Interessenkonflikte/Sponsoring beschrieben? - ja (Bx-Gerät)	2(+/-)
Peltier et al. MRI-targeted biopsies versus systematic transrectal ultrasound guided biopsies for the diagnosis of localized prostate cancer in biopsy naïve men. Biomed Res Int. 2015	n=110 bx-naive pat.s with a clinical suspicion of PCa due to an abnormal PSA and/or DRE Mar.2012 -Sep.2013	prebiopsy mpMRI with targeted biopsies when a lesion was found and standard systematic biopsies (12-18 cores) in all pat.	cohort analysis (single centre analysis) csPCa definition: presence of any core with a GSC > 3 + 3 and/or a maximal cancer core length ≥ 6mm	The number of men diagnosed with csPCa was 50 (45%) with the TAR protocol versus 32 (29%) with the STD protocol. The proportion of cores positive for csPCa in TAR cores was 28.9% versus 9.8% for STD cores (p<0.001). TAR-bx missed 1 case of csPCa found with STD-bx STD-bx missed 14 cases of csPCa found with TAR-bx	Studientyp - (pro/retro?) cohort analysis Patientencharakteristika beschrieben (Tabelle)? - ja ausbalanciert zwischen den Gruppen? - n.a. Drop-out beschrieben/Consort-Diagramm? - n.a. Statistische Methoden beschrieben? - ja angewendete Methoden und Definitionen beschrieben (z. B. Schmerzskala, Definition von Schmerz, Messmethoden etc.) - ja ITT-Analyse? - n.a. Interessenkonflikte/Sponsoring beschrieben? - ja (keine)	2(+/-)
Baco et al. A Randomized Controlled Trial To Assess and Compare the Outcomes of Two-core Prostate Biopsy Guided by Fused Magnetic Resonance and Transrectal Ultrasound Images and Traditional 12-core Systematic Biopsy. Eur Urol 2016	n=183 bx-naive pat. (final analysis 175) 1:1 random alloc. Sept.2011 -June2013	MRI/TRUS-TB on lesions with PIRADS score 3–5 on MRI, followed by 12-core RB (neg.MRI=PIRADS 1–2: only 12-core RB) control group: if a palpable and/or TRUS suspicious lesion was found, two targeted bx from the lesion followed by 12-core RB	randomized controlled trial (single centre analysis) csPCa defined as cancer volume 0.5 ml for Gleason 6 disease or any cancer volume for Gleason ≥7	no significant difference between the MRI and control groups in the overall detection rate of any cancer (59% vs 54%, p = 0.4) or detection of csPCa (44% vs 49%, p=0.5). Detection of csPCa was comparable between two-core MRI/TRUS-TB (38%) and 12-core RB in the control group (49%; p=0.2) In the MRI group, seven tumors (7/51; 14%) were not detected on MRI and three tumors (6%) weremissed on TB. A total of five missed cancers (5/51; 10%) were csPCa. RB (after TB in MRI group) missed three cancers (two GSC 7 and one GSC 6), all of which were detected by TB	Studientyp - RCT Patientencharakteristika beschrieben (Tabelle)? - ja ausbalanciert zwischen den Gruppen? - ja Drop-out beschrieben/Consort-Diagramm? - ja Statistische Methoden beschrieben? - ja angewendete Methoden und Definitionen beschrieben (z. B. Schmerzskala, Definition von Schmerz, Messmethoden etc.) - ja ITT-Analyse? - (ja) Interessenkonflikte/Sponsoring beschrieben? - ja (keine)	1-
Panebianco et al. Multiparametric magnetic resonance imaging vs. standard care in men being evaluated for prostate cancer: a randomized study. Urol Oncol 2015	n = 1,140 pat.s (bx‐naive) ‐ group A: n=570 ‐ group B: n=570 Oct.2011 -Mar.2014	group A: TRUS‐bx (14 cores) group B: mpMRI followed by standard bx + targeted bx (if MRI‐suspicious lesions present) group A: pat.s w/o findings in first bx: see group B pat.s w/o suspicous MRI lesions: saturation bx	randomized controlled trial (single centre analysis) PCa cutoff: GSC ≥6	group A: detection of PCa by first standard bx in 37% (210/570) of pat.s ‐ neg.standard bx followed by MRI: 59% suspicious ‐ of these, PCa detected in 88% by targeted + standard bx ‐‐ neg.MRI followed by saturation bx: detection of PCa in 29% group B: MRI‐suspicious lesions in 77% ‐ of these, PCa detected in 93% (440/570) by targeted + standard bx ‐ neg.MRI followed by standard bx and saturation bx: detection of PCa in 28%	Studientyp - RCT Patientencharakteristika beschrieben (Tabelle)? - nein ausbalanciert zwischen den Gruppen? - unklar Drop-out beschrieben/Consort-Diagramm? - (nein) Statistische Methoden beschrieben? - ja angewendete Methoden und Definitionen beschrieben (z. B. Schmerzskala, Definition von Schmerz, Messmethoden etc.) - ja ITT-Analyse? - n.a. Interessenkonflikte/Sponsoring beschrieben? - unklar	1-
Tonttila et al. Prebiopsy Multiparametric Magnetic Resonance Imaging for Prostate Cancer Diagnosis in Biopsy-naive Men with Suspected Prostate Cancer Based on Elevated Prostate-specific Antigen Values: Results from a Randomized Prospective Blinded Controlled Trial. Eur Urol 2016	n=130 bx-naive pat.s (PSA<20ng) - MRI group n=65 (n=53 per protocol) - control n=65 (n=60 per protocol) April2011 -Dec.2014	Patients in the MP-MRI group underwent prebiopsy MP-MRI followed by TRUS-guided RB and cognitive MRI/TRUS fusion TB. Patients in the control group underwent routine TRUS-guided RB (10-12 cores) alone.	randomized controlled trial ausschließen wg. cognitive? csPCa definition: Gleason score >3+3, more than two positive cores, or maximum cancer core length 3mm	CDR between the MP-MRI and control groups in the ITT population was similar (37 of 62 [60%] vs 36 of 63 [57%]; difference was 2.5% [95% CI 14-19]; p=0.8 per protocol analysis: The detection rate for csPCa and the detection rate for clin. insignificant PCa were similar between the MP-MRI (standard bx + tbx) and control groups (55% [29 of 53] vs 45% [27 of 60]; 9.7% difference [95% CI 8.5-27]; p=0.8; and 9.4% [5 of 53] vs 12% [7 of 60]; 2.2% difference [95% CI 14-10]; p = 0.5)	Studientyp - RCT Patientencharakteristika beschrieben (Tabelle)? - ja ausbalanciert zwischen den Gruppen? - ja Drop-out beschrieben/Consort-Diagramm? - ja Statistische Methoden beschrieben? - ja angewendete Methoden und Definitionen beschrieben (z. B. Schmerzskala, Definition von Schmerz, Messmethoden etc.) - ja ITT-Analyse? - ja, sowie per-protocol Interessenkonflikte/Sponsoring beschrieben? - ja (keine)	1-
Ahmed H. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017 Jan 19. [Epub ahead of print]	n = 576 pat.s (bx-naive)	standardized MRI, then combined bx procedure: TPM-bx (template prostate mapping, 50-60 cores) followed by TRUS-bx (10-12 cores) [no targeted bx of MRI-suspicious regions]	prospective study (multicentre) csPCa definition: GSC ≥4+3 or maximum cancer core length 6 mm or longer bereits für 2. TK extrahiert; Studie wegen Ablauf als methodisch schwierig eingeschätzt: nach dem MRT keine gezielte Bx; Referenztext war TPM-Bx (mit 50-60 cores), erst danach SBx -- diese ist bei einer durchlöcherten Prostata vermutlich nicht mehr aussagekräftig / vergleichbar. keine gezielte Bx der MRT-Läsionen, SE und SP für die MRT selbst (mit TPM als Referenz) ggf. brauchbar - nur nicht zum SBx-Vergleich)	detection of PCa on TPM-bx in 71% of pat.s (prevalence of csPCa: 40%) 27% had a negative mpMRI, of whom 10,8% had csPCa on TPM-bx scenario of MRI as triage test: suspicious (Likert ≥3) would get bx (either standard bx or guided by MRI, assuming similar accuracy to TPM) - 27% would avoid primary bx	Studientyp - prospective paired-cohort study Patientencharakteristika beschrieben (Tabelle)? - ja (supp.data) ausbalanciert zwischen den Gruppen? - n.a. Drop-out beschrieben/Consort-Diagramm? - ja Statistische Methoden beschrieben? - ja angewendete Methoden und Definitionen beschrieben (z. B. Schmerzskala, Definition von Schmerz, Messmethoden etc.) - ja ITT-Analyse? - (ja) Interessenkonflikte/Sponsoring beschrieben? - ja (technical devices and trials)	2(+)

5.2.2 EvT 5.17

Zitat	Population	Suchstrategie	eingeschlossene Studien	Heterogenität	Ergebnisse	methodische Validität	LoE
Wegelin O. Comparing Three Different Techniques for Magnetic Resonance Imaging-targeted Prostate Biopsies: A Systematic Review of In-bore versus Magnetic Resonance Imaging-transrectal Ultrasound fusion versus Cognitive Registration. Is There a Preferred Technique? Eur Urol 2016.	primary diagnostic studies reporting on PCa detection rates among pat.s at risk of PCa using MRI-TB, or FUS-TB, or COG-TB n = 43 articles relevant for review question n = 25 studies reporting on both MRI-GB (any technique) and TRUS-GB results separately within same population inclusion of publications up to Oct.2014	A comprehensive search of literature (PubMed, Embase, and CENTRAL databases; range of last 10y) was performed. The search terms used were ‘‘Prostate OR Prostatic Neoplasm’’ AND ‘‘Biopsy’’ AND ‘‘Magnetic Resonance Imaging OR Image-Guided Biopsy’’	Published primary diagnostic studies reporting on PCa detection rates among patients at risk of PCa using MRI-TB, or FUS-TB, or COG-TB were included.	Heterogenität: The 43 included studies demonstrate significant variation in cohort size, ranging from 16 to 1003 (median, 106) patients. The mean PSA value ranged from 5.1 ng/ml to 15.3 ng/ml and the mean age ranged from 61.8 yr to 70.0 yr. The populations varied with respect to biopsy history. For all subsequent analysis, we used clinical homogenous data on detection rates among patients with no or negative prior biopsies. Considerable heterogeneity was found with respect to the applied definition of csPCa. Furthermore, several studies did not present a definition of csPCa, and consequently did not report data on the detection of csPCa.	PCa-suspekte MRI-Befunde in 73% der Pat.; Studien (n=6) mit Bx-naiven in 68%, mit vorheriger neg.Bx (n=7 Studien) in 79% Werte für Studien mit Bx-naiv sowie prev.neg.bx gepoolt: MRI-GB and TRUS-GB did not significantly differ in overall PCa detection, rel. sensitivity of 0.98 (95% CI: 0.90-1.07) - SE for MRI-GB: 0.81 ( 0.76-0.85) - SE for TRUS-GB: 0.83 (0.77–0.88) --> MRI-GB missed 19% of all cancers, while TRUS-GB missed 17%. MRI-GB detected significantly more csPCa than TRUS-GB, rel. sensitivity of 1.16 (1.02-1.32) - SE for MRI-GB: 0.90 (0.85-0.94) - SE for TRUS-GB: 0.79 (0.68-0.87) --> MRI-GB missed 10% significant cancers whilst TRUS-GB missed 21% no significant advantage of usage of any one technique of MRI-GB (cognitive / fusion / in-bore) for the detection of csPCa	1. a priori Design - nein 2. Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3. Literaturrecherche min 2 Datenbanken + 1 Zusatz - ja 4. graue Literatur eingeschl. - nein 5. Vollständige Liste ein- und ausgeschl. Studien - nein 6. Details der eingeschlossenen Studien - ja 7. Qualität der eingeschlossenen Studien bewertet - ja 8. In Conclusion Hinweise auf methodische Qualität - ja 9. Heterogenität erhoben?- ? 10. Publication bias (funnel plot) - nein 11. CoI / funding für Review UND für alle Studien berichtet - nein AMSTAR-Score 5-6/11	2+ Aussagen zu MRI-tbx vs. Sbx keine Metaanalyse für Bx-naive Subgruppe (Daten könnten ggf. extrahiert werden)

Zitat	Charakteristika	Ergebnisse	Methodische Bewertung AMSTAR	LoE
Gayet M. The value of magnetic resonance imaging and ultrasonography (MRI/US)-fusion biopsy platforms in prostate cancer detection: a systematic review. BJU Int 2016;117(3):392-400.	systematic review of prospective non-randomised controlled trials or in-patient control studies Suchzeitraum: 01/2004-02/2015 (Begründung: Zulassung von fusion-Plattformen 2004) Population: Bx-naive und Pat. mit vorheriger negativer Bx mit Verdacht auf PCa Vergleichsgruppen: standard Bx (überwiegend 10-12 Stanzen) or another way of MRI-guided TB Endpunkte: (clinically significant) prostate CDRs per patient body of evidence: 11 eingeschl. Studien, 2602 eingeschl. Pat. (min 20, max 1003)	Ergebnisse: CDRs für alle PCa zwischen 35,7-79,5% bei fusion Bx vs. 28,5-56,6% bei Standard-Bx. CDRs für klinisch signifikante PCa zwischen 17,2-47,9% bei fusion Bx vs. 12,2-38% bei Standard-Bx. Sicherheit: nicht erhoben / berichtet author's conclusion: No clear advantage of MRI/US fusion-guided TBs was seen for cancer detection rates (CDRs) of all prostate cancers. However, MRI/US fusion-guided TBs tended to give higher CDRs for clinically significant prostate cancers in our analysis. Important limitations of the present systematic review include: the limited number of included studies, lack of a general definition of ‘clinically significant’ prostate cancer, the heterogeneous study population, and a reference test with low sensitivity and specificity. Although MRI/US-fusion TB has proved its value in men with prior negative biopsies, general use of this technique in diagnosing prostate cancer should only be performed after critical consideration. Before bringing MRI/US fusion-guided TB in to general practice, there is a need for more prospective studies on prostate cancer diagnosis.	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - nein 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - (ja) 4 Bericht über Ausschlüsse - ja 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - ja 9 Heterogenität erhoben?- ja 10 Publication bias berichtet (funnel plot/verbal) - nein 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 7/11	2+
Wu J. Is magnetic resonance/ultrasound fusion prostate biopsy better than systematic prostate biopsy? An updated meta- and trial sequential analysis. Oncotarget 2015;6(41):43571-80.	Metaanalyse mit 16 paired cohort studies (in-patient control) Suchzeitraum: bis Mai 2015 Population: Pat. mit Verdacht auf PCa; keine Unterscheidung, ob Bx-naiv oder nicht Interventionen: MRI-TRUS fusion Bx Vergleichsgruppen: standard biopsy (überwiegend (10-)12 core Bx) Endpunkte: Detektion von PCa body of evidence: 16 eingeschl. Studien, 3105 eingeschl. Pat. (30-1003, jedoch überwiegend kleine Studien)	Heterogenität: moderat (I^2 = 28%) Ergebnisse/Effektivität: es wurden signifikant mehr PCa detektiert mit MRI-US fusion: risk ratio 1,06 (95% KI 1.01-1,12; p=0,03) Subgruppenanalysen: bei moderatem/hohem Verdacht im MRI lag das risk ratio bei 1,46 (95% KI 1.28-1,67; p<0,001; I^2 = 0). bessere Ergebnisse auch bezogen auf klin. signif. PCa: RR 1,19 (95% KI 1.10-1,29; p<0,01; I^2 = 0) Sicherheit: nicht berichtet Qualität der Evidenz für einzelne Outcomes: s. I^2-Werte; geringer Publikationsbias author's conclusion: We found that, although more evidence is needed, MR/US fusion prostate biopsy alone detected more prostate cancers than systematic biopsy and was better than systematic biopsy in detecting clinically significant prostate cancers. For those men with moderate/high suspicion in mp-MRI, MR/US fusion biopsy showed a great advantage.	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - nein 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - ?(3 DB) 4 Bericht über Ausschlüsse - ja 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - nein 9 Heterogenität erhoben?- ja 10 Publication bias berichtet (funnel plot/verbal) - ja 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 6-7/11	2+
Valerio M. Detection of Clinically Significant Prostate Cancer Using Magnetic Resonance Imaging-Ultrasound Fusion Targeted Biopsy: A Systematic Review. Eur Urol 2015;68(1):8-19.	Systematic review mit v.a. paired cohort studies (in-patient control) Suchzeitraum: bis Dez. 2013 body of evidence: 15 eingeschl. Studien (davon 14 paired cohort design) (+ Bericht über 7 weitere nicht-publ.), 2293 eingeschl. Pat. (13-582) Population: Pat. in 3 Studien Bx-naiv, in 3 Studien vorherige negative TRUS-Bx, in 8 Studien gemischt Interventionen: MRI-TRUS fusion Bx Vergleichsgruppen: current standard of TRUS biopsy (10-12 Stanzen) (no adequate reference test in any of the studies) Endpunkte: Detektionsrate klin. signif. PCa (jeweils definiert in Studien, z.T. unterschiedlich)	Ergebnisse Effektivität: The median detection of clinically significant disease was 23,6% (range 4,8-52%) for standard biopsy and 33,3% (13,2-50%) for MRI-TRUS fusion. Across all studies in which both rates were reported, fusion Bx allowed the detection of greater numbers of clinically significant cancers compared to standard Bx. The absolute difference in detection rates was a median of 6,8% (0,9-41,4%) always in favour of fusion Bx. Considering absolute differences, fusion Bx detected a median of 9,1% (5-16,2%) additional clinically significant cancers that were missed by standard Bx alone. Detektion PCa insgesamt (signifikant / insignifikant): ähnliche Werte (allerdings in 4 Studien höhere Detektionsraten mit Standard-TRUS) Efficiency: The median difference in number of cores needed to detect one man with clinically significant cancer was 32,1 cores in favour of the targeted approach. Sicherheit: AEs nur in 2 Studien berichtet, davon in 1 nicht vorgekommen, in der anderen nicht zu unterscheiden, welches Verfahren zu AE geführt hat. Heterogenität der eingeschl. Populationen vorhanden (wird als positiv diskutiert: Erhöhung der externen Validität) Qualität der Evidenz für einzelne Outcomes: most studies had low RoB and low applicability concerns with respect to pat. selection. In four studies the index test domain demonstrated a high RoB and applicability concern. Limitations: 1) the definition of clinically significant disease varied between studies.2) it was not possible to determine the overall accuracy of a MRI-TRUS image fusion approach because an accurate reference test was not used. author's conclusion: mpMRI-US fusion targeted Bx detect more clinically significant cancers using fewer cores compared with standard Bx. [findings need to be confirmed by large multicentre validating studies]	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - ja 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - ja 4 Bericht über Ausschlüsse - ja 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - ja 9 Heterogenität erhoben?- nein 10 Publication bias berichtet (funnel plot/verbal) - nein 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 7/11	2+
Schoots IG. Magnetic resonance imaging-targeted biopsy may enhance the diagnostic accuracy of significant prostate cancer detection compared to standard transrectal ultrasound-guided biopsy: a systematic review and meta-analysis. Eur Urol 2015;68(3):438-50.	Metaanalyse von ausschl. Studien mit beiden Interventionen / Methoden beim selben Pat. (in-patient-control studies) Suchzeitraum: bis Mai 2014 Population: Pat. mit positivem MRI (keine Einschränkungen bzgl. Alter) Interventionen: MRI-targeted biopsy und TRUS-Bx (8-12 Stanzen), jeweils im selben Pat. Vergleichsgruppen: jeweils derselbe Pat. mit MRI-TBx und (davon unabh.) TRUS-Bx (überwiegend 10-12 Stanzen) Endpunkte: detection of PCa (significant, insignificant - hier jedoch unterschiedl. Definitionen in den Studien) by MRI-TBx vs. TRUS-Bx body of evidence: 16 eingeschl. Studien, 1926 eingeschl. Pat. (Studien: 7x MRI-visual / 10x -fusion / 1x -in-bore)	Heterogenität untersucht bzgl. patient recruitment (initial Bx / prev.neg. / mixed); navigational system (MRI-visual / -fusion / -in-bore), jeweils bezogen aufeinander. Heterogenität (I^2 >40%) in den meisten Analysen vorhanden Ergebnisse: keine signifikanten Unterschiede zwischen MRI-TBx und TRUS-Bx bzgl. overall PCa-Detektion (Sensitivität: 0,85; 95%-KI: 0,80-0,89 bzw. 0,81 und 0,70-0,88) MRI-TBx and TRUS-Bx did not significantly differ in overall prostate cancer detection, with a relative sensitivity of 1.05 (95% CI 0.94–1.19) MRI-TBx and TRUS-Bx missed the diagnosis of prostate cancer in 15% and 19% of cases, respectively, with a concordance between the tests of 65% (54–74%). relevante Subgruppenanalysen: relative Sensitivität von MRI-fusion/TRUS =1,09, d.h. höhere Detektion durch MRI-fusion, jedoch hohe Heterogenität (I^2 89) bzgl. signifikantem PCa: relative Sensitivität MRI-fusion /TRUS=1,29 Subgruppe Pat. mit vorhergehender negativer Biopsie: relative Sensitivität 1,54 (vs. 1,10 bei initialer Biopsie) author's conclusion: In men with clinical suspicion of prostate cancer and a suspicious lesion seen on multiparametric MRI, MRI-TBx and TRUS-Bx did not differ in overall detection of prostate cancer. However, MRI-TBx had a higher rate of detection of potentially significant prostate cancer and a lower rate of detection of insignificant prostate cancer compared to the standard TRUS-Bx. Subgroup analysis showed that MRI-TBx improved the detection of significant prostate cancer in men with a previous negative biopsy, rather than in men with an initial biopsy. However, we found significant heterogeneity, which limits the strengths of the conclusions that can be made. Furthermore, as a consequence of underlying methodological flaws of MRI-TBx, the comparison to standard systematic biopsy needs to be regarded with caution.	1 Protokoll/Suchstrategie/ Fragestellung vorhanden - nein 2 Selektion und Extraktion durch 2 unabh. Bearbeiter - ja 3 Literaturrecherche min 2 Datenbanken + 1 Zusatz - ja 4 Bericht über Ausschlüsse - ? (We excluded unpublished data or abstracts because information that is needed to correctly assess the study quality and interpret the results was not available in abstracts.) 5 Vollständige Liste der ein- und ausgeschlossenen Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschlossenen Studien bewertet - ja 8 In Conclusion Hinweise auf methodische Qualität - ja 9 Heterogenität erhoben?- ja 10 Publication bias berichtet (funnel plot/verbal) - ja 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score: 7/11	2+

5.2.2 EvT 5.19

Autoren, Jahr,
Studientyp

Untersuchte Studien/ Materialien

Welche Behandlungen wurden geprüft

Charakteristik eingeschlossener Studien /
Befunde in Bezug auf Therapiewirkungen

Literaturbelege

Evidenzniveau (SIGN)

Krause BJ et al, 2011
systematischer Review

Literatur-recherche in Medline (Pubmed) 2000-2/2010

Suchbegriffe : « prostate », « choline » « PET », «positron emission tomography » k.A. zu sprachlichen Eingrenzungen

Diagnose – inbesondere Staging und Restaging des Prostatakarzinoms durch Positronenemissionstomographie mittels [11 C] und [18F] Cholin-Derivaten

Eingeschlossen wurden Originalpublikationen, keine weiteren Einschlusskriterien angegeben

Nur Ergebnisse für Diagnose und Staging/Restaging dargestellt.
1. Cholin-PET und Cholin-PET/CT zur Primärdiagnostik/zum lokalen Staging

Detektion hohe Sensitivität (PET/CT :

Reske SN et al, 2006
ROC Area under the curve 0,89 +/-0,01 für SUV (mean standard uptake) cut-off 2,65 für korrekte Prädiktion eines PCas.

Detektion niedrige Sensitivität (PET/CT) :

Farsad et al, 2005, Giovacchini et al, 2008, Martorana et al, 2006, Scher et al, 2007.

Befund in allen Studien : SUVs benigne und maligne sind zwar tendentiell unterschiedlich (höhere SUV bei Malignität) es gibt aber eine substantielle Überlappung

2. Cholin-PET und Cholin PET/CT zur Festlegung des Lymphknotenstatus

Daten aus 5 Studien (3 PET, 2 PET/CT).

Sensitivität : 61% (Mittelwert, KI n.a.)

Spezifität : 96% (Mittelwert, KI n.a.)

3. Cholin-PET und Cholin PET/CT zur Diagnostik/zum Staging bei Rezidiv (18F und 11C-Choline-PET und PET/CT)

Angabe der Autoren: oft kleine Fallzahlen, retrospektive Erhebungen, verschiedene Tracer, und Systeme, Fehlen von histologische Befunden.

Zu beachten sind Limitationen bei der Erkennung sehr kleiner Befunde

Daten aus 19 Studien (2003-2010), Einzelstudie n=9-358, 4/19Studien mind. N=100; 1115 Pat. nach RPE (80%) , 240 Pat. nach EBRT

Detektion des Lokalrezidivs/der Lymphknoten und der Fernmetastasen gemeinsam ausgewertet.

Sensitivität: 39%-100%, Mittelwert 70,7%

Fallzahl der Studien mit 100%: 9,15,25 (Schmid et al, 2005, Scattoni et al, 2007, Rinnab et al, 2008

Sensitivität Studien mind. n=100: 39%, 47%, 54%, 85% (Castellucci et al, 2009, Cimitan et al, 2006,Picchio et al, 2003, Giovacchini et al, 2010)

Giovacchini et al. benutzten Nomogramm zusätzlich (Alter Gleason Score, PSA-WErt , pT-Kategorie etc.)

Spezifität: (Daten aus 8 Studien) 0-100%, Mittelwert 65,3%

4. Bewertung des Therapieansprechens (nicht dargestellt)

1a. PET :
de Jong IJ, Pruim J, Elsinga PH, et al. Eur Urol 2002;42: 18–23. Kotzerke J, Prang J, Neumaier B, et al. Eur J Nucl Med 2000; 27:1415–9. Kwee SA, Coel MN, Lim J, Ko JP. J Urol 2005; 173: 252–5. Kwee SA, Wei H, Sesterhenn I, et al. J Nucl Med 2006;47: 262–9. Sutinen E, Nurmi M, Roivainen A, et al. Eur J Nucl Med Mol Imaging 2004;31:317–24. Yamaguchi T, Lee J, Uemura H, et al. Eur J Nucl Med Mol Imaging 2005;32:742– 8. Yoshida S, Nakagomi K, Goto S, et al. Urol Int 2005; 74:214 –20.

1b PET/CT :
Farsad M, Schiavina R, Castellucci P, et al. J Nucl Med 2005;46:1642–9. Giovacchini G, Picchio M, Coradeschi E, et al. Eur J Nucl Med Mol Imaging 2008; 35:1065–73.Martorana G, Schiavina R, Corti B, et al. J Urol 2006;176:954–60, Discussion 60. Reske SN, Blumstein NM, Neumaier B, et al. J Nucl Med 2006; 47: 1249 –54. Scher B, Seitz M, Albinger W, et al. Eur J Nucl Med Mol Imaging 2007; 34:45–53. Schmid DT, John H, Zweifel R, et al. Radiology 2005;235: 623–8.

2a. PET: de Jong IJ, Pruim J, Elsinga PH, et al. J Nucl Med 2003;44:331–5. Kotzerke J, Prang J, Neumaier B, et al. Eur J Nucl Med 2000; 27:1415–9.
2b. PET/CT: Husarik DB, Miralbell R, Dubs M, et al. Eur J Nucl Med Mol Imaging 2008;35:253 ; Schiavina R, Scattoni V, Castellucci P, et al. Eur Urol 2008 Aug:392 –401.

3a. 11C-Choline-PET
de Jong IJ, Pruim J, Elsinga PH, et al. Eur Urol 2003;44:32– 8 Picchio M, Messa C, Landoni C, et al. J Urol 2003;169:1337– 40. Breeuwsma AJ, Pruim J, van den Bergh AC, et al. Int J Radiat Oncol Biol Phys 2010;77:160–4.
3b. 11C-Choline-PET/CT
Castellucci P, Fuccio C, Nanni C, et al. J Nucl Med 2009; 50:1394–400. Krause BJ, Souvatzoglou M, Tuncel M, et al. Eur J Nucl Med Mol Imaging 2008;35:18 –23. Reske SN, Blumstein NM, Glatting G. Eur J Nucl Med Mol Imaging 2008 Jan;35:9 –17. Rinnab L, Mottaghy FM, Blumstein NM, et al. BJU Int 2007;100:786 –93. Scattoni V, Picchio M, Suardi N, et al. Eur Urol 2007;52: 423–9. Giovacchini G, Picchio M, Coradeschi E, et al. Eur J Nucl Med Mol Imaging 2010;37:301–9.
3c. 18F-FCH-PET/CT
Schmid DT, John H, Zweifel R, et al. Radiology 2005;235: 623–8. Heinisch M, Dirisamer A, Loidl W, et al. Mol Imaging Biol 2006;8:43– 8. Husarik DB, Miralbell R, Dubs M, et al. Eur J Nucl Med Mol Imaging 2008;35:253– 63. Cimitan M, Bortolus R, Morassut S, et al. Eur J Nucl Med Mol Imaging 2006;33:1387-98 Vees H, Buchegger F, Albrecht S, et al. BJU Int 2007 ;99: 1415–20. Pelosi E, Arena V, Skanjeti A, et al. Radiol Med 2008;113 :895– 904. Steiner C, Vees H, Zaidi H, et al Nuklearmedizin 2009; 48 : 1–9.

5.3 EvT 5.21

Artikel (Autor, Jahr) / Studientyp	Anzahl der Patienten/ Patientenmerkmale	Intervention/ ggf. Nachverfolgung	Vergleichsintervention Referenzstandard	Outcomes	Ergebnisse	Bemerkungen	Evidenzniveau SIGN
Manikandan R. et al, 2007 Retrospektive unizentrische Fallserie UK	N=144 von 204 Patienten mit PCa cT1 2002-2005 und MRT vor RPE Mittl. Alter 62,5J Mittl. PSA 8,73 11% Gleason > 7	1,5 T MRT mit T1- und T2 gewichteter Auswertung 3-6mm Schichtdicke keine endorektale Spule Keine Angabe über Malignitätskriterien und Scoring	Referenz-Standard: Histologie aus OP-Präparat bei 71 Patienten	MRT klinische Relevanz (Änderung der Strategie) , Falsch Negative bei 71 Pat.	Insgesamt 95,14% (137/144) MRT ohne Nachweis von kaplseüberschreitendem Tumor 5 MRT unklar (4,86%) : in weiterern Untersuchungen in 3 Fällen duch gezielte Biopsie lokal begrenzt bestätigt In 2 Fällen upstaging aufgrund des MRT –Befunds zu T3 – Änderung der Therapie, keine Operation bei 1,3% 22/71 mit RPE mitpT3: Falsch negativ-Rate des MRT 30,9% (22/71)		3
Nogueira L. et al, 2010 Retrospektive unizentrische Fall-Kontroll-Studie Angabe zu Interessenkonflikten: k.A:	n = 202 Pat. mit präoperativ low-rik Prostatakarzinom (nur 1 Biopsie positive <2mm, Gleason 4/5, =cT2a, PSA-Dichte <0,1, PSA-Wert n.a.	MRT T2 gewichtete Auswertung bei 50 % (n=101) mit „indolent cancer“ nach RPE : Gleason4/5, organbegrenzt, Tumorvolumen <0,5ml, negative Schnittränder 81% multifokal 68% bilateral	MRT T2 gewichtete Auswertung bei 50% (n=101) mit „non indolent cancer“ nach RPE (höherer Gleason Score, nicht organbegrenzt, Tumorvolumen >0,5ml, positive Schnittränder Referenz standard: Histologie aus Prostatektomie-präparat „whole mount section“ 4mm	Sensitivität, Spezifität des MRT bezogen auf die Tumorlokalisation stratifiziert nach 4 Regionen (Links anterior, links posterior, rechts anterior, rechts posterior)	Postoperative Klassifikation p-Kategorie indolent: pT0 13% sonst pT2 p-Kategorie non indolent: pT2 79% >/= pT3 21% MRT Sensitivität: 2%-20% pro Region MRT Spezifität: 91-95% pro Region MRT Sensitivität Kapselüberschreitung: 58% MRT Spezifität Kapselüberschreitung: 100% Prädiktive Werte nicht aufgeführt, Konfidenzintervalle sehr weit!!	Anmerkung der Autoren: Testgüte MRT ist nicht ausreichend, um Patienten für fokale Therapie zu identifizieren	2-3
Turkbey B. et al, 2010 Prospektive? Unizentrische Fallserie Angabe zu Interessenkonflikten: keine finanziellen IK	N=70 6/2004-12/2007 mittl. Alter 60,4J (40-75), mittl. PSA-Wert 5,47ng/ml (1-19,9) mit PCa (Histologie aus Biopsie), mittl Gleason 7 (6-9) Ausschlusskriterien: KI für MRT oder keine Platzierung einer endorektalen Sonde möglich	MRT/MRS und diff. gew. MRT, „six channel cardiac coil“ + endorektale Spule 3T Auswerter wussten, dass Pat. PCa hatten, sonst keine Informationen Suspekt: T2w: gut abgegrenzte runde-ellipsoide Form mit niedriger Intensität + Beurteilung ECE +Samenblaseninvasion MRS: Choline/Citrate-Ratio suspekt bei >3SD Abweichung zu Gesunden (vorher an Testset n=44 evaluiert); ab 0,373 TZ nicht beurteilt. DCE-MRT: suspekt bei früher und intensiver Anreicherung mit schnellem Washout	Referenz standard: Histologie aus Prostatektomie-präparat „whole mount section“ direkter Schnittvergleich angestrebt 2 Vorgehensweisen: 1. „stringent approach“ 2. „neighbouring approach“ - auch jeweils Nachbarregion wegen pot. Distortion berücksichtigt	Sensitivität,Spezifität bezüglich korrekter Lokalisation von Karzinomfoki Testgüte des Staging	20% (14/70) wegen Hämorrhagie nicht beurteilbar 25% Tumoren in TZ 34% max. 3mm Sensitivität: T2w: 42% [95%KI 36-47] T2w (neighbouring approach): 73% [95KI 67-78] DCE-MRT: 18% [95%KI 13-23] MRS: 13% [95%KI 8-18] Spezifität T2w: 83% [95%KI 81-86] T2w (neighbouring approach): 89% [95%KI 85-93] DCE-MRT: 96% [95%KI 94-97] MRS: 97% [95%KI 96-98] Sensitivität für Tumoren >3mm signifikant höher Sensitivität für Tumoren höherem Gleasonscore Trend höher n.s. Staging (Nachweis ECE): Sensitivität: 78,2% Spezifität: 80,9% Accuracy: 80% Nur „MRT imaging“ angegeben Staging Nachweis Samenblaseninfiltration: Sensitivität: 80% Spezifität: 97% Accuracy: 95,7% Nur „MRT imaging“ angegeben	Keine absoluten Zahlen angegeben	3
Weinreb J.C. et al, 2009 Prospetive multizentrische Fallserie IK: 2 der Autoren als Berater der unterstüztenden MRT-Firmen (von den anderen “kontrolliert”	N= 110 von 134 rekrutierten Patienten aus 7 Institutionen 2/2004-6/2005 im Mittel 58J , mittl PSA 5,9(0,7-44) Ausschluss vorherige Systemtherapie, metallische Implantate u.andere KI MRT	MRT/MRS mind. 6 Wo nach Biopsie mit endorektaler Spule 3-6mm T1,T2-Wichtung und MRS Kriterien Malignität: Signalintensität, Choline+Creatinine/Citrat-Ratio und Choline/Citrat-Ratio Scoring 1-5 (5= sicher maligne) + Lokalisation des Tumors	Nur MRT Referenz-standard: Histologie aus Prostatektomie Schnitte Analysiert von Studien-Pathologen (22“whole mount“, 88“standard blocks“)	AUC für Tumorlokalisaton mittels MRT/MRS	Bildqualität der 110 MRT durch Expertenpanel beurteilt: MRT: alle ok MRS: 21 schlecht, 6 ungenügend 32% der Tumoren <0,5cm³ 41% bis 2cm³ 37% >2cm³ Accuracy Lokalisation PCa nach Sextant: AUC MRT: 0,60 (pro Befunder 0,57-0,62) AUC MRT+MRS: 0,58 (pro Befunder 0,54-0,60) n.s. Bei 2 Befundern sign schlechter mit MRS	7 akademische Zentren in den USA, alle MRTvon 8 Befundern in 7 Institutionen ausgewertet mit 2-10J Erfahrung - aber viele keine Erfahrung für MRS vor Beginn endorektale Test-MRT/MRS mit Phantom, hands on Training, einheitliches Protokoll	2+-3

Artikel
(Autor, Jahr) /
Studientyp

Anzahl der Patienten/
Patientenmerkmale

Intervention/
ggf. Nachverfolgung

Vergleichsintervention
Referenzstandard

Outcomes

Ergebnisse

Bemerkungen

Evidenzniveau

SIGN

Manikandan R. et al, 2007

Retrospektive unizentrische Fallserie

N=144 von 204 Patienten mit PCa cT1 2002-2005 und MRT vor RPE

Mittl. Alter 62,5J

Mittl. PSA 8,73

11% Gleason > 7

1,5 T MRT mit T1- und T2 gewichteter Auswertung 3-6mm Schichtdicke keine endorektale Spule

Keine Angabe über Malignitätskriterien und Scoring

Referenz-Standard: Histologie aus OP-Präparat bei 71 Patienten

MRT klinische Relevanz (Änderung der Strategie) , Falsch Negative bei 71 Pat.

Insgesamt 95,14% (137/144) MRT ohne Nachweis von kaplseüberschreitendem Tumor

5 MRT unklar (4,86%) : in weiterern Untersuchungen in 3 Fällen duch gezielte Biopsie lokal begrenzt bestätigt

In 2 Fällen upstaging aufgrund des MRT –Befunds zu T3 – Änderung der Therapie, keine Operation bei 1,3%

22/71 mit RPE mitpT3:

Falsch negativ-Rate des MRT 30,9% (22/71)

Nogueira L. et al, 2010

Retrospektive unizentrische Fall-Kontroll-Studie

Angabe zu Interessenkonflikten: k.A:

n = 202 Pat. mit präoperativ low-rik Prostatakarzinom (nur 1 Biopsie positive <2mm, Gleason 4/5, =cT2a, PSA-Dichte <0,1, PSA-Wert n.a.

MRT T2 gewichtete Auswertung bei

50 % (n=101) mit „indolent cancer“ nach RPE : Gleason4/5, organbegrenzt, Tumorvolumen <0,5ml, negative Schnittränder

81% multifokal
68% bilateral

MRT T2 gewichtete Auswertung bei 50% (n=101) mit „non indolent cancer“ nach RPE (höherer Gleason Score, nicht organbegrenzt, Tumorvolumen >0,5ml, positive Schnittränder

Referenz
standard: Histologie aus Prostatektomie-präparat „whole mount section“

4mm

Sensitivität, Spezifität des MRT bezogen auf die Tumorlokalisation stratifiziert nach 4 Regionen (Links anterior, links posterior, rechts anterior, rechts posterior)

Postoperative Klassifikation

p-Kategorie indolent:

pT0 13% sonst pT2

p-Kategorie non indolent:

pT2 79%

>/= pT3 21%

MRT Sensitivität:

2%-20% pro Region

MRT Spezifität:
91-95% pro Region

MRT Sensitivität Kapselüberschreitung: 58%

MRT Spezifität Kapselüberschreitung: 100%

Prädiktive Werte nicht aufgeführt, Konfidenzintervalle sehr weit!!

Anmerkung der Autoren: Testgüte MRT ist nicht ausreichend, um Patienten für fokale Therapie zu identifizieren

2-3

Turkbey B. et al, 2010

Prospektive? Unizentrische Fallserie

Angabe zu Interessenkonflikten: keine finanziellen IK

N=70

6/2004-12/2007
mittl. Alter 60,4J (40-75), mittl. PSA-Wert 5,47ng/ml (1-19,9) mit PCa (Histologie aus Biopsie), mittl Gleason 7 (6-9)

Ausschlusskriterien: KI für MRT oder keine Platzierung einer endorektalen Sonde möglich

MRT/MRS und diff. gew. MRT,

„six channel cardiac coil“ + endorektale Spule 3T

Auswerter wussten, dass Pat. PCa hatten, sonst keine Informationen

Suspekt:

T2w: gut abgegrenzte runde-ellipsoide Form mit niedriger Intensität + Beurteilung ECE +Samenblaseninvasion

MRS: Choline/Citrate-Ratio suspekt bei >3SD Abweichung zu Gesunden (vorher an Testset n=44 evaluiert); ab 0,373 TZ nicht beurteilt.

DCE-MRT: suspekt bei früher und intensiver Anreicherung mit schnellem Washout

Referenz
standard: Histologie aus Prostatektomie-präparat „whole mount section“ direkter Schnittvergleich angestrebt

2 Vorgehensweisen:

1. „stringent approach“

2. „neighbouring approach“ - auch jeweils Nachbarregion wegen pot. Distortion berücksichtigt

Sensitivität,Spezifität bezüglich korrekter Lokalisation von Karzinomfoki

Testgüte des Staging

20% (14/70) wegen Hämorrhagie nicht beurteilbar

25% Tumoren in TZ

34% max. 3mm

Sensitivität:
T2w: 42% [95%KI 36-47]
T2w (neighbouring approach): 73% [95KI 67-78]

DCE-MRT: 18% [95%KI 13-23]

MRS: 13% [95%KI 8-18]

Spezifität
T2w: 83% [95%KI 81-86]
T2w (neighbouring approach): 89% [95%KI 85-93]
DCE-MRT: 96% [95%KI 94-97]

MRS: 97% [95%KI 96-98]

Sensitivität für Tumoren >3mm signifikant höher

Sensitivität für Tumoren höherem Gleasonscore Trend höher n.s.
Staging (Nachweis ECE):

Sensitivität: 78,2%
Spezifität: 80,9%

Accuracy: 80%

Nur „MRT imaging“ angegeben

Staging Nachweis Samenblaseninfiltration:
Sensitivität: 80%
Spezifität: 97%
Accuracy: 95,7%
Nur „MRT imaging“ angegeben

Keine absoluten Zahlen angegeben

Weinreb J.C. et al, 2009

Prospetive multizentrische Fallserie

IK: 2 der Autoren als Berater der unterstüztenden MRT-Firmen (von den anderen “kontrolliert”

N= 110 von 134 rekrutierten Patienten aus 7 Institutionen
2/2004-6/2005
im Mittel 58J , mittl PSA 5,9(0,7-44)

Ausschluss vorherige Systemtherapie, metallische Implantate u.andere KI MRT

MRT/MRS mind. 6 Wo nach Biopsie
mit endorektaler Spule 3-6mm

T1,T2-Wichtung und MRS

Kriterien Malignität: Signalintensität, Choline+Creatinine/Citrat-Ratio und Choline/Citrat-Ratio

Scoring 1-5 (5= sicher maligne) + Lokalisation des Tumors

Nur MRT

Referenz-standard:
Histologie aus Prostatektomie

Schnitte Analysiert von Studien-Pathologen (22“whole mount“, 88“standard blocks“)

AUC für Tumorlokalisaton mittels MRT/MRS

Bildqualität der 110 MRT durch Expertenpanel beurteilt:

MRT: alle ok

MRS: 21 schlecht, 6 ungenügend

32% der Tumoren <0,5cm³

41% bis 2cm³
37% >2cm³

Accuracy Lokalisation PCa nach Sextant:

AUC MRT: 0,60 (pro Befunder 0,57-0,62)

AUC MRT+MRS: 0,58 (pro Befunder 0,54-0,60) n.s.

Bei 2 Befundern sign schlechter mit MRS

7 akademische Zentren in den USA,

alle MRTvon 8 Befundern in 7 Institutionen ausgewertet mit 2-10J Erfahrung - aber viele keine Erfahrung für MRS

vor Beginn endorektale Test-MRT/MRS mit Phantom, hands on Training, einheitliches Protokoll

2+-3

5.3 EvT 5.23

Studientyp	Autoren, Jahr	untersuchte Studien/ Materialien	Welche diagnostischen Interventionen wurden geprüft?	Welcher Referenzstandard wurde herangezogen?	Ergebnisse (Testgüte-Parameter)	Bemerkungen	LoE	Literaturbelege
Syst. Review/ Metaanalyse	Abuzallouf, 2004	48 Studien aus systematischer Suche 1966 bis 2002, 25 Publikationen zu CT von Beckenlymphknoten, Patienten mit neudiagnostiziertem noch nicht anbehandeltem PCA	Diagnostik von Metastasen bei neudiagnostiziertem ProstataCa. Hier dargestellt: 1. CT zum N-Staging: Testgüte-Parameter im Vergleich zu histologischem Befund; Wahrscheinlichkeit von N+ (CT-morphologisch und histologisch) in Abhängigkeit von PSA, T-Stadium und Gleason (Knochenszintigraphie s.u.)	Lymphknoten-Histologie bzw. CT-Befund	Prävalenz: histologisch positives N-Stadium in 654 von 4264 Patienten (15,3%) Prävalenz: positiver CT-Befund in 105 von 4264 Patienten (2,5%) Testgüte-Parameter CT vs. Histologie: Sensitivität: 16% Spezifität: 100% PPW:: 97% NPW*: 87% Prävalenz von positiven CT-Befunden bei PSA<20 ng/ml: 0% (0,0-1,0%) PSA>20 ng/ml: 1,1% (0,2-3,2%) T1/2: 0,6% (0,3-1,2%) T3/4: 19,5% (14,2-26,0%) Gleason<7: 1,2% (0,7-1,91%) Gleason>7: 12,5% (8,5-17,6%) Prävalenz von histologischen N+ bei PSA<20 ng/ml: 5,5% (4,7-6,3%) PSA>20 ng/ml: 26,5% (23,3-30,0%) T1/2: 7,8% (6,9-8,7%) T3/4: 25,7% (21,1-30,9%) Gleason<7: 6,6% (5,3-8,3%) Gleason>7: 22,8% (14,4-33,4%)	Schlussfolgerung der Autoren: „Pelvic CT appears warranted for patients with a Gleason score of 8 or greater, or locally advanced disease. In these clinical scenarios such investigations would be indicated. Although patients with increased PSA are at risk for pelvic adenopathy, CT appears poorly able to detect this condition.”	2++	6,8,9,11,16,25,35-55

Studientyp

Autoren, Jahr

untersuchte Studien/ Materialien

Welche diagnostischen Interventionen wurden geprüft?

Welcher Referenzstandard wurde herangezogen?

Ergebnisse

(Testgüte-Parameter)

Bemerkungen

LoE

Literaturbelege

Syst. Review/
Metaanalyse

Abuzallouf,
2004

48 Studien aus systematischer Suche 1966 bis 2002, 25 Publikationen zu CT von Beckenlymphknoten, Patienten mit neudiagnostiziertem noch nicht anbehandeltem PCA

Diagnostik von Metastasen bei neudiagnostiziertem ProstataCa.

Hier dargestellt:

CT zum N-Staging: Testgüte-Parameter im Vergleich zu histologischem Befund;

Wahrscheinlichkeit von N+ (CT-morphologisch und histologisch) in Abhängigkeit von PSA, T-Stadium und Gleason

(Knochenszintigraphie s.u.)

Lymphknoten-Histologie bzw. CT-Befund

Prävalenz: histologisch positives N-Stadium in 654 von 4264 Patienten (15,3%)

Prävalenz: positiver CT-Befund in 105 von 4264 Patienten (2,5%)

Testgüte-Parameter CT vs. Histologie:

Sensitivität: 16%

Spezifität: 100%

PPW*:: 97%

NPW**: 87%

Prävalenz von positiven CT-Befunden bei

PSA<20 ng/ml: 0% (0,0-1,0%)

PSA>20 ng/ml: 1,1% (0,2-3,2%)

T1/2: 0,6% (0,3-1,2%)

T3/4: 19,5% (14,2-26,0%)

Gleason<7: 1,2% (0,7-1,91%)

Gleason>7: 12,5% (8,5-17,6%)

Prävalenz von histologischen N+ bei

PSA<20 ng/ml: 5,5% (4,7-6,3%)

PSA>20 ng/ml: 26,5% (23,3-30,0%)

T1/2: 7,8% (6,9-8,7%)

T3/4: 25,7% (21,1-30,9%)

Gleason<7: 6,6% (5,3-8,3%)

Gleason>7: 22,8% (14,4-33,4%)

Schlussfolgerung der Autoren: „Pelvic CT appears warranted for patients with a Gleason score of 8 or greater, or locally advanced disease. In these clinical scenarios such investigations would be indicated. Although patients with increased PSA are at risk for pelvic adenopathy, CT appears poorly able to detect this condition.”

2++

6,8,9,11,16,25,35-55

5.3 EvT 5.24

Studientyp	Autoren, Jahr	untersuchte Studien/ Materialien	Welche diagnostischen Interventionen wurden geprüft?	Welcher Referenzstandard wurde herangezogen?	Ergebnisse (Testgüte-Parameter)	Bemerkungen	LoE	Literaturbelege
Syst. Review/ MetaAnalyse	Abuzallouf, 2004	48 Studien aus systematischer Suche 1966 bis 2002, 25 Publikationen zu CT von Beckenlymphknoten, Patienten mit neudiagnostiziertem noch nicht anbehandeltem PCA	Diagnostik von Metastasen bei neudiagnostiziertem ProstataCa. Hier dargestellt: 1. CT zum N-Staging: Testgüte-Parameter im Vergleich zu histologischem Befund; Wahrscheinlichkeit von N+ (CT-morphologisch und histologisch) in Abhängigkeit von PSA, T-Stadium und Gleason (Knochenszintigraphie s.u.)	Lymphknoten-Histologie bzw. CT-Befund	Prävalenz: histologisch positives N-Stadium in 654 von 4264 Patienten (15,3%) Prävalenz: positiver CT-Befund in 105 von 4264 Patienten (2,5%) Testgüte-Parameter CT vs. Histologie: Sensitivität: 16% Spezifität: 100% PPW:: 97% NPW*: 87% Prävalenz von positiven CT-Befunden bei PSA<20 ng/ml: 0% (0,0-1,0%) PSA>20 ng/ml: 1,1% (0,2-3,2%) T1/2: 0,6% (0,3-1,2%) T3/4: 19,5% (14,2-26,0%) Gleason<7: 1,2% (0,7-1,91%) Gleason>7: 12,5% (8,5-17,6%) Prävalenz von histologischen N+ bei PSA<20 ng/ml: 5,5% (4,7-6,3%) PSA>20 ng/ml: 26,5% (23,3-30,0%) T1/2: 7,8% (6,9-8,7%) T3/4: 25,7% (21,1-30,9%) Gleason<7: 6,6% (5,3-8,3%) Gleason>7: 22,8% (14,4-33,4%)	Schlussfolgerung der Autoren: „Pelvic CT appears warranted for patients with a Gleason score of 8 or greater, or locally advanced disease. In these clinical scenarios such investigations would be indicated. Although patients with increased PSA are at risk for pelvic adenopathy, CT appears poorly able to detect this condition.”	2++	6,8,9,11,16,25,35-55

Studientyp

Autoren, Jahr

untersuchte Studien/ Materialien

Welche diagnostischen Interventionen wurden geprüft?

Welcher Referenzstandard wurde herangezogen?

Ergebnisse

(Testgüte-Parameter)

Bemerkungen

LoE

Literaturbelege

Syst. Review/
MetaAnalyse

Abuzallouf,
2004

48 Studien aus systematischer Suche 1966 bis 2002, 25 Publikationen zu CT von Beckenlymphknoten, Patienten mit neudiagnostiziertem noch nicht anbehandeltem PCA

Diagnostik von Metastasen bei neudiagnostiziertem ProstataCa.

Hier dargestellt:

CT zum N-Staging: Testgüte-Parameter im Vergleich zu histologischem Befund;

Wahrscheinlichkeit von N+ (CT-morphologisch und histologisch) in Abhängigkeit von PSA, T-Stadium und Gleason

(Knochenszintigraphie s.u.)

Lymphknoten-Histologie bzw. CT-Befund

Prävalenz: histologisch positives N-Stadium in 654 von 4264 Patienten (15,3%)

Prävalenz: positiver CT-Befund in 105 von 4264 Patienten (2,5%)

Testgüte-Parameter CT vs. Histologie:

Sensitivität: 16%

Spezifität: 100%

PPW*:: 97%

NPW**: 87%

Prävalenz von positiven CT-Befunden bei

PSA<20 ng/ml: 0% (0,0-1,0%)

PSA>20 ng/ml: 1,1% (0,2-3,2%)

T1/2: 0,6% (0,3-1,2%)

T3/4: 19,5% (14,2-26,0%)

Gleason<7: 1,2% (0,7-1,91%)

Gleason>7: 12,5% (8,5-17,6%)

Prävalenz von histologischen N+ bei

PSA<20 ng/ml: 5,5% (4,7-6,3%)

PSA>20 ng/ml: 26,5% (23,3-30,0%)

T1/2: 7,8% (6,9-8,7%)

T3/4: 25,7% (21,1-30,9%)

Gleason<7: 6,6% (5,3-8,3%)

Gleason>7: 22,8% (14,4-33,4%)

2++

6,8,9,11,16,25,35-55

Artikel (Autor, Jahr, Journal)	Studientyp prospektiv/retrospektiv	Anzahl der Patienten	Patientenmerkmale	Diagnostische Intervention	Referenzstandard	Ergebnisse (Testgüteparameter)	Bemerkungen	Evidenz-Niveau (SIGN)
Ayyathurai, 2006	Retrospektive Fallserie/ Querschnitt	124	Bioptisch gesichertes PCA, T1-4	Knochenszinti	Keiner	Prävalenz positiver Szintigraphien: 20 von 124 (16,1%) Prävalenz steigt mit höherem T-Stadium, Gleason und PSA	Autoren verleichen ihre Ergebnisse mit verschiedenen Risiko-stratefizierungseinteilungen	3

Artikel
(Autor, Jahr, Journal)

Studientyp
prospektiv/retrospektiv

Anzahl der Patienten

Patientenmerkmale

Diagnostische Intervention

Referenzstandard

Ergebnisse

(Testgüteparameter)

Bemerkungen

Evidenz-Niveau (SIGN)

Ayyathurai,
2006

Retrospektive Fallserie/ Querschnitt

124

Bioptisch gesichertes PCA, T1-4

Knochenszinti

Keiner

Prävalenz positiver Szintigraphien: 20 von 124 (16,1%)

Prävalenz steigt mit höherem T-Stadium, Gleason und PSA

Autoren verleichen ihre Ergebnisse mit verschiedenen Risiko-stratefizierungseinteilungen

Hofman_Lancet_2020

Hofman MS, Lawrentschuk N, Francis RJ et al. Prostate-specific membrane antigen PET-CT in patients with high-risk prostate cancer before curative-intent surgery or radiotherapy (proPSMA): a prospective, randomised, multicentre study. Lancet. 2020 Apr 11;395(10231):1208-1216. doi: 10.1016/S0140-6736(20)30314-7.

Link

https://pubmed.ncbi.nlm.nih.gov/32209449/

Assessment

(Risk of bias Tool)

Selection bias

randomization: low

concealment and unpredictability: low

Performance bias

blinding of participants and staff: high

Detection bias

blinding of evaluation: unclear

Attrition bias

lost to follow-up: low

ITT-analysis: low

Reporting bias

selective result presentation: low

Other bias

conflict of interest/ sponsoring: low

comment: baseline characteristics - overall median age (IQR) was 69.0 years (63.0–73.5), control group: 68.0 years (62.5–72.0) vs. intervention group: 70.0 years (64.0–74.0)

Imaging was interpreted by experienced radiologists and nuclear medicine specialists, some of whom were further involved with the trial.

Design

randomized controlled trial

Australia, 10 hospitals

recruitment between March 22, 2017, to Nov 2, 2018

Australian New Zealand Clinical Trials Registry, ANZCTR12617000005358 (proPSMA)

Population

Inclusion criteria:

1. Untreated, biopsy-proven adenocarcinoma of the prostate

2. Patient is being considered for curative-intent treatment with radical prostatectomy or radiotherapy

3. Patients must have high-risk features including at least one of the following features:

o PSA ≥ 20.0 ng/ml within 12 weeks prior to randomisation

o Gleason grade group 3, 4 or 5

o Clinical stage ≥ T3

4. Age ≥ 18 years

5. Patient has provided written informed consent for participation in this trial

6. In the opinion of investigator, willing and able to comply with required study procedures

Exclusion criteria:

1. Patient has had any prior therapy for prostate cancer

2. Patient has undergone, within 8 weeks prior to randomisation, imaging for the primary purpose of staging pelvic nodal or distant metastatic disease of prostate cancer

3. A history of other active malignancy within the last 2 years, with the exception of non-melanoma skin cancer or melanoma in-situ

4. Prostate cancer with significant sarcomatoid or spindle cell or neuroendocrine small cell components

5. Significant intercurrent morbidity that, in the judgment of the investigator, would limit compliance with study protocols

Intervention

gallium-68 PSMA-11 PET-CT

Control

conventional imaging with CT and bone scanning

comment: first-line imaging was done within 21 days following randomization

patients crossed over unless three or more distant metastases were identified

Outcome(s)

Primary endpoint

- detection of metastatic disease (accuracy - area under the curve (AUC) of the receiver operating characteristic curve)

(first-line imaging, pelvic nodal (N) or distant metastatic (M) disease)

Secondary endpoints

- line diagnostic imaging on choice of therapy

- occurrence of equivocal study results

- occurrence of patients who were upstaged by second-line diagnostic imaging or detection of additional metastases

- impact of second-line diagnostic imaging on choice of therapy

- time to clinical treatment failure defined by biochemical failure, development of metastatic disease or commencement of salvage therapy

- total cost of diagnostic evaluation

- total patient radiation exposure (mSv)

- reporter agreement in interpretation of on-site readers providing clinical care and those of the central imaging laboratory readers

- number of adverse events

Results

n=302 men were randomly assigned (n(C)=152 vs. n(I)=150)

- two patients withdrew before first-line imaging and were replaced

- median age 69.0 (IQR 63.0-73.5) years

- median PSA 10.2 (IQR 6.6-17.1) ng/mL

- ISUP grade 5 n=131 (44%)

- 295 (98%) men with follow-up

- pelvic nodal or distant metastatic disease: n=87 (30%)

primary outcome:

Diagnostic accuracy to detect pelvic or nodal distant metastatic disease:

	First line PSMA PET/CT (I) n=145	First line Conventional Imaging (C) n=150
True positive	34	18
False positive	2	9
False negative	6	29
True negative	103	94
Missing	3	2
Sensitivity (95% CI)	85% (74% - 96%)	38% (24%-52%)
Specificity (95% CI)	98% (95% - 100%)	91% (85%-97%)
Accuracy (95% CI)	94% (91%-98%)	75% (68%-82%)
AUC (95% CI)	92% (88% - 95%)	65% (60%-69%)

AUC=area under the curve, CI=confidence interval

secondary outcomes:

impact on choice of therapy: (I vs C, n (95% CI))

- change in management intent or modality, or change in modality delivery: n=41 (28%; 21–36) vs n=23 (15%; 10–22), p=0.008

equivocal findings: (I vs C, n (%; 95% CI))

- total n=11 [7%; 4–13] vs n=35 [23%; 95% CI 17–31], p<0.0001

- pelvic nodal n=2 [1%, 0-5] vs n=9 [6%; 3–11], p=0.0047

- distant metastases n=10 [7%, 3-12] vs n=32 [21%; 15–28], p<0.0001

patients who were upstaged: (I vs C n (%; 95% CI))

- change of stage after second-line imaging: n=33 (22% [16–30]) vs n=20 (14% [95% CI 9–22)

- change in stage correct (compared with reference standard): n=26 (18% [12–25]) vs n=3 (2% [0–6])

time to clinical treatment failure: -

total cost of diagnostic evaluation: -

total patient radiation exposure (mSv): median (IQR), I vs C, n=148 vs. n=152

- first line scan (mSv), total 11.9 (8.1, 17.5); 8.0 (7.2, 9.2) vs 17.4 (15.3, 21.9)

- CT radiation (mSv), total 6.6 (4.7, 9.5); 7.0 (4.5, 9.2) vs 6.5 (5.0, 10.1)

- bone scan (mSv), total 10.7 (9.3, 12.2); 10.7 (9.2, 12.1) vs 10.6 (9.4, 12.3)

- PSMA PET/CT (mSv), total 8.0 (7.2, 9.3); 8.0 (7.2, 9.2) vs 8.0 (7.1, 9.3)

- second line scan (mSv), total 11.2 (7.9, 18.0); 18.1 (15.6, 21.0) vs 8.0 (7.1, 9.3)

- first and second line scan (mSv), 25.7 (22.1, 30.4); 25.7 (21.9, 29.8) vs 25.6 (22.1, 31.4)

reporter agreement in interpretation:

- PSMA PET-CT:

- nodal disease (κ=0.87 [95% CI 0.81–0.94])

- distant disease (κ=0.88 [95% CI 0.84–0.92]

number of adverse events:

- no adverse events to ⁶⁸Ga-PSMA-11 were reported

Comments

- n=152 patients received to first-line CT and bone scan, n=148 patients received first-line imaging – these patients were included in secondary endpoint analysis; n=150 vs. n=145 were included in the primary endpoint analysis (authors documented n=1 patient classified as lost-to-follow-up in each group, as well as n=2 patients in the PSMA-PET-CT group withdrew after second-line imaging)

- The reference standard regarding the presence of pelvic nodal or distant metastases was determined by each site’s principal investigator at 6 months (plus or minus 30 days) after randomisation using a predefined composite panel encompassing histopathologic, imaging, clinical, and biochemical findings.

5.3 EvT 5.27

Zitat	Studienpopulation	Intervention	Studiendesign	Ergebnisse	methodische Bewertung	LoE
Maurer T. Diagnostic Efficacy of (68)Gallium-PSMA Positron Emission Tomography Compared to Conventional Imaging for Lymph Node Staging of 130 Consecutive Patients with Intermediate to High Risk Prostate Cancer. J Urol 2016;195(5):1436-43.	pat.s before RPx + pLND median 66y (range 61-72); PSA 11,55 ng/mL (0,57-244); GSC 7 (6-10); 56,7% ≥cT3 2012-2014 single-center study (Germany)	68Ga-PSMA (median dose 1,76MBq/kg), PET(/MR or /CT, n=95 vs. 35) 1h after injection	retrospective study (n=130 pat.s, 734 regional LNs dissected) comparison: CT, MRT control: histology	detection of LNMs in 31,5% of pat.s (histologically detected metastases in 15,9% of dissected LNs) pat.-based sensitivity 65,9%; specificity 98,9%; PPV 96,4%; NPV 86,3%; accuracy 88,5% with PSMA (vs. morphological imaging: 43,9%; 85,4%; 58,1%; 76,8%; 72,3%) (p=0,002) template-based sensitivity of PSMA-PET: 73,5%; specificity 99,2%; PPV 94,5%; NPV 95,2%; accuracy 95,1% (vs. morphological imaging: 28,2%; 97,1; 64,7%; 87,7%; 86,1%) (p<0,001) lesion detection in primary tumor: tracer uptake in 91,6%. in pat.s where PET was false-negative for LNs, there was no PSMA uptake in primary tumor either. mean maximum size of LNMs missed in PET was 3±1mm (range 1-5)	Pat.-Charakteristika beschrieben - ja ausbalanciert zwischen den Gruppen - n/a drop-out beschrieben - n/a statist. Methoden beschrieben - ja Methoden, Definitionen beschrieben - ja ITT-Analyse - ja / n/a CoI /Sponsoring angegeben - nein Quadas: low - low - low - low	3
Budaus L. Initial Experience of (68)Ga-PSMA PET/CT Imaging in High-risk Prostate Cancer Patients Prior to Radical Prostatectomy. Eur Urol 2016;69(3):393-6.	pat.s before RPx +epLND (LNM risk >20%) mean 62,3y, median 63y (44-75); PSA mean 38,9 ng/mL, median 8,8 (1,4-376); GSC 7: 63,3% (>7: 36,7%); 63,3% ≥cT3 2014-2015 multi-center / pat.s from 5 sites (Germany)	68Ga-PSMA (mean dose 169 MBq, range 106-269), PET ?h after injection (maybe different at incl. sites)	retrospective study (n=30 pat.s, 608 LN systematically dissected during prostatectomy) (pat.s pre-selected for homogeneity: risk for LNMs >20% each) control: histology	detection of LNMs in 40% of pat.s (metastases in 8,7% of dissected LNs) pat.based sensitivity 33,3%; specificity 100%; PPV 100%; NPV 69,2%; accuracy 73,3% lesion-based sensitivity 27,3%; specificity 100%; PPV 100%; NPV 52,9% correct prediction of prostate tumor foci in 92,9% pat.s [33,3% of pat.s true positive with Ga-PSMA, false negative: 66,7%]; median size of Ga-PSMA-detected vs. undetected LNMs: 13,6 vs 4,3 mm (p<0,05) conclusion: substantial influence of LNM size on the diagnostic accuracy of 68Ga-PSMA PET/CT	Pat.-Charakteristika beschrieben - ja ausbalanciert zwischen den Gruppen - n/a drop-out beschrieben - n/a statist. Methoden beschrieben - nein Methoden, Definitionen beschrieben - nein ITT-Analyse - ja / n/a CoI /Sponsoring angegeben - ja Quadas: high - low - low - low	3-
van Leeuwen PJ. Prospective Evaluation of 68Gallium-PSMA Positron Emission Tomography/Computerized Tomography for Preoperative Lymph Node Staging in Prostate Cancer. BJU Int 2016.	pat.s before RP+LND mean/median 65y (range 60-71), PSA mean 8,2 ng/mL, median 8,1 (5,2-10,1); GSC 7: 17% (8-9: 83%); 20% cT3 / 60% cT2 / 20% cT1c 2015 single-center study (Australia)	68Ga-PSMA (mean dose 150 MBq) PET 1h after injection	prospective study (n=30 pat.s, 536 resected LNs following standard procedure) control: histology	detection rates: 37% of pat.s with LNMs (metastases in 4,9% of dissected LNs) pat.-based sensitivity 64%, specificity 95%, PPV 88%, NPV 82% LN-based: sensitivity 58%, specificity 100%, PPV 94%, NPV 98% conclusion: In patients with intermediate to high-risk PC, 68Ga-PSMA PET/CT has a high specificity and a moderate sensitivity for LNM detection. [detection depends on LNM size (sensitivity better if >5mm) (mean size true positive: 4,7mm, false negative 2,7mm)]	Pat.-Charakteristika beschrieben - ja ausbalanciert zwischen den Gruppen - n/a drop-out beschrieben - n/a statist. Methoden beschrieben - ja Methoden, Definitionen beschrieben - ja ITT-Analyse - ja / n/a CoI /Sponsoring angegeben - ja Quadas: low - low - low - low	2(+/-)
Herlemann A. Ga-PSMA Positron Emission Tomography/Computed Tomography Provides Accurate Staging of Lymph Node Regions Prior to Lymph Node Dissection in Patients with Prostate Cancer. Eur Urol 2016.	pat.s for LN staging before RP+LND, or before secondary LND; primary LND: mean 70,5y (59-80); mean PSA 55,9 ng/mL (3,3-363); GSC ≥7: 90% [data split for initial (here) / recurrent (below)] 2014-2015 single-center study (Germany)	68Ga-PSMA (mean dose ?MBq) PET 1h after injection	prospective study (n=34 pat.s total, primary LND pat. n=20, 235 dissected LNs from 40 regions) comparison: CT control: histology	(overall (pLND+sLND) detection of LNM: sensitivity 84%, specificity 82%, PPV 84%, NPV 82% for PSMA-PET (vs. 65%, 76%, 75%, 67% for CT)) primary LND per region: sensitivity 86%; specificity 88%; PPV 80%; NPV 92%; accuracy 88% (vs CT before pLND: 64%; 81%; 64%; 81%; 75%)	Pat.-Charakteristika beschrieben - ja ausbalanciert zwischen den Gruppen - n/a drop-out beschrieben - ja statist. Methoden beschrieben - nein Methoden, Definitionen beschrieben - ja ITT-Analyse - ja / n/a CoI /Sponsoring angegeben - ja Quadas: low - low - low - low	2(+/-)

Zitat	eingeschlossene Studien	Intervention	Suchstrategie, Ein- und Ausschlusskriterien	Ergebnisse	Methodische Bewertung AMSTAR	LoE
Perera et al. Eur Uro 2016 Sensitivity, specificity, and predictors of positive 68Ga-PSMA PET in advanced prostate cancer: a systematic review and meta-analysis	16 included studies for metaanalysis - 1 prospective, 15 retrospective studies - 2 studies for primary staging - 8 for BCR or progression staging - 6 studies with mixed groups (5 with histology-proven disease) primary outcome: to identify predictors of 68Ga-PSMA PET positivity secondary outcome measure: sensitivity and specificity of 68Ga-PSMA PET–positive lesions in advanced prostate cancer	68Ga-PSMA PET scan for prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy)	Scientific literature databases (MEDLINE, EMBASE, ScienceDirect, Cochrane Libraries, and Web of Science) were systematically searched in April 2016 Studies evaluating the utility of 68Ga-PSMA PET in detection of metastatic disease in advanced prostate cancer were included for analysis. Study designs considered for inclusion were clinical trials, prospective studies, and retrospective cohorts or comparative series. Studies assessing the diagnostic utility of 68Ga-PSMA PET in prostate cancer staging (before definitive treatment) or staging for recurrent disease (following therapy) were included for assessment.	70.7% of 68Ga-PSMA PET scans were positive; by cohort type, 40% (95% CI 19–64%) of scans were positive for patients undergoing primary staging and 76% (95% CI 66– 85%) for those undergoing secondary staging In assessing disease recurrence, PSMA PET positivity increased with the PSA category: for PSA <0.2 ng/ml, the pooled estimate was 42%, which increased to 58%, 76%, and 95% for the 0.2–0.99, 1.00–1.99, and >2.00 ng/ml PSA subgroups, respectively PSAdt: the pooled PSMA positivity was 64% for PSAdt 6 mo and 92% for PSAdt <6 mo diagnostic accuracy (per-lesion analysis): summary sensitivity 80%, specificity 97% limitations: high heterogeneity between groups and within all subgroups (I2 > 70%)	1 Protokoll/Fragestellung vorhanden - nein 2 unabh. Selektion und Extraktion - ja 3 Lit.recherche min 2 Datenbanken + 1 Zusatz - nein 4 Bericht über Ausschlüsse - nein 5 Vollst. Liste der ein- und ausgeschl. Studien - nein 6 Details der eingeschlossenen Studien - ja 7 Qualität der eingeschl. Studien bewertet - ja 8 In Conclusion Hinweise auf method. Qualität - ja 9 Heterogenität erhoben?- ja 10 Publicat. bias berichtet (funnel plot/verbal) - ja 11 CoI/funding für Review UND für alle Studien berichtet - nein --> AMSTAR-Score 6/11	2+

5.4.3.1 EvT 5.42

Autor, Jahr	Definition von insignifikant	Vorhersage mittels	Patienten	Ergebnis
Kattan 2003	≤0,5 cc, organbegrenzt, keine gering differenzierten Elemente.	Kattan-Nomogramm (PSA, Prostata-Volumen, cT, GS).	409	20% mit bestätigtem insignifikantem PCa; ROC 0,64-0,79.

5.4.3.1 EvT 5.44

Autor, Jahr	Definition von insignifikant	Vorhersage mittels	Patienten	Ergebnis
Kattan 2003	≤0,5 cc, organbegrenzt, keine gering differenzierten Elemente.	Kattan-Nomogramm (PSA, Prostata-Volumen, cT, GS).	409	20% mit bestätigtem insignifikantem PCa; ROC 0,64-0,79.

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