The role of MRI and PET/CT in the primary staging of newly diagnosed prostate cancer: a systematic review of the literature

Raisa S Abrams-Pompe; Stefano Fanti; Ivo G Schoots; Caroline M Moore; Baris Turkbey; Andrew J Vickers; Jochen Walz; Thomas Steuber; James A Eastham

doi:10.1016/j.euo.2020.11.002

. Author manuscript; available in PMC: 2022 Oct 26.

Published in final edited form as: Eur Urol Oncol. 2020 Dec 4;4(3):370–395. doi: 10.1016/j.euo.2020.11.002

The role of MRI and PET/CT in the primary staging of newly diagnosed prostate cancer: a systematic review of the literature

Raisa S Abrams-Pompe ^1,², Stefano Fanti ³, Ivo G Schoots ⁴, Caroline M Moore ⁵, Baris Turkbey ⁶, Andrew J Vickers ⁷, Jochen Walz ⁸, Thomas Steuber ¹, James A Eastham ⁹

PMCID: PMC9597893 NIHMSID: NIHMS1840630 PMID: 33272865

Abstract

Context:

The management of newly diagnosed prostate cancer (PCa) is guided in part by accurate clinical staging. The role of imaging, including magnetic resonance imaging (MRI) and positron emission tomography/computed tomography (PET/CT) in initial staging remains controversial.

Objective:

To systematically review studies of MRI and/or PET/CT in the staging of newly diagnosed PCa with respect to tumor (T), nodal (N) and metastasis (M), TNM staging.

Evidence acquisition:

We performed a systematic review of the literature using MEDLINE and Web of Science databases between 2012 and 2020 following the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement guidelines.

Evidence synthesis:

A total of 139 studies (83 on T, 47 on N and 24 on M status) were included. Ninety-nine (71%) were retrospective, 39 (28%) prospective and one was a randomized controlled trial (RCT). Most studies on T staging examined MRI, while PET/CT was primarily used for N and M staging. Sensitivity for detection of extraprostatic extension, seminal vesicle invasion or lymph node invasion ranged widely. When imaging was incorporated into existing risk tools, gain in accuracy was observed in some studies, although these findings have not been replicated. For M staging, most favorable results were reported for prostate specific membrane antigen (PSMA) PET/CT, which demonstrated significantly better performance than conventional imaging.

Conclusions:

A variety of studies on modern imaging techniques for TNM staging in newly diagnosed PCa exist. For T and N staging, reported sensitivity of imaging such as MRI or PET/CT varied widely due to data heterogeneity, small sample size and low event rates resulting in large confidence intervals and high level of uncertainty. Therefore, uniformity in data presentation and standardization on this topic is needed. The most promising technique for M staging, which was recently evaluated in an RCT, is PSMA-PET/CT.

Patient summary:

We performed a systematic review of currently available imaging modalities to stage newly diagnosed PCa. With respect to local tumor and lymph node assessment, performance of imaging ranged widely. However, PSMA-PET/CT showed favorable results for detection of distant metastases.

Keywords: Prostate cancer, extraprostatic extension, lymph node metastases, metastases, staging, imaging, magnetic resonance imaging, Positron emission tomography, PSMA-PET/CT

1. Introduction

While localized prostate cancer (PCa) is curable using surgery or radiatiotherapy, cure remains unlikely in the presence of metastatic disease. Therefore, appropriate assessment of the extent of PCa at diagnosis is critical in guiding initial treatment.

Current guidelines recommend abdominopelvic imaging as well as bone scintigraphy in selected men with intermediate- and in all men with high-risk disease.¹ Unfortunately, conventional imaging with computed tomography (CT) and bone scintigraphy suffer from a lack of sensitivity and specificity in identifying metastatic cancer, which has prompted the search for new imaging techniques with better diagnostic accuracy.² For local tumor and lymph node staging, multiparametric magnetic resonance imaging (mpMRI) has gained more and more attention. In 2012, the European Society of Urogenital Radiology (ESUR) standardized MRI reporting by introducing the Prostate Imaging Reporting and Data System (PI-RADS) and updated this version in collaboration with the American College of Radiology to PIRADS v2 in 2015.³

Hybrid positron emission tomography/computed tomography (PET/CT) or PET/MRI combines the advantages of morphological and anatomical information derived by CT/MRI with additional functional (metabolic/biochemical activity) information provided by PET. By using MRI instead of CT, ionization radiation is spared. Newer tracers, such as 18F-Sodiumfluoride- (NaF-), 18F-/11C-choline, 18F-fluciclovine (FACBC), and 68Ga-labelled prostate specific membrane antigen (PSMA) have recently been developed and further analyzed. Introduced in 2012, the 68Ga-labelled PSMA-targeted radio-ligand Glu-NH-CO-NH-Lys-[68Ga-(HBED-CC)] (68Ga- PSMA-HBED-CC or 68Ga-PSMA-11) revolutionized PCa imaging. PSMA, a large extracellular type-2 transmembrane glycoprotein, is highly overexpressed in PCa and can easily be targeted by this ligand for imaging purposes.⁴

While PET/CT is already widely adopted within staging of recurrent PCa, only few studies reported on its role for primary staging.⁵

This prompted us to perform a systematic review of the current literature on modern imaging types for TNM staging of newly diagnosed PCa.

2. Evidence Acquisition

2.1. Search strategy

The following search strategy was used as keywords and/or free texts: (“prostate cancer” OR “prostate neoplasm”) AND (“MRI” OR “PET CT”) AND (“staging” OR “tumor stage” OR “lymph nod*” OR “metastas*”). Furthermore, cited references from selected articles and from review articles retrieved in the search were screened for additional information. All abstracts were screened by two independent reviewers (RSAP) and (JE) using a newly developed standardized data form. Any disagreements were resolved by open discussion. Based on title and abstract selection, full texts were analyzed in more detail for eligibility.

The validated Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) scoring system was used to assess risk of bias.⁷

2.2. Study selection

Inclusion criteria followed the Patient Index test Comparator Outcomes Study (PICOS) design. Therefore, studies were assessed considering patients with biopsy-proven, newly diagnosed PCa (P) who underwent MRI and/or PET CT (I) for further disease assessment (O) with respect to T (tumor), N (lymph node) and M (distant metastases) status. Only original articles and brief correspondences were included (S). Most studies did not have a comparator (C) group. In some, conventional imaging such as contrast CT or bone scintigraphy served as comparator. In some, MRI was directly compared to PET/CT. For T and N staging, only studies with histological confirmation by radical prostatectomy (RP) or pelvic lymph node dissection (PLND) as “gold” standard of reference were included. T stage included extent of tumor beyond the capsule (≥pT3), while studies analyzing index tumor, tumor detection or localization of primary tumor were not considered. For M staging, a best value comparator, mostly derived by panel decision considering clinical, biochemical and imaging data at baseline and follow-up was used. In some studies, M status was additionally confirmed by histology, e.g. via bone biopsy. Studies without best value comparator or histological confirmation were excluded. The search was limited to English-language articles. Articles that reported results of subgroups for primary staging separately were included while articles with mixed results of staging and re-staging purposes were excluded.

2.3. Data extraction

From each selected study, we extracted first author, year of publication, study design, imaging type, imaging technique (including tracer or sequences), total number of patients analyzed, main patient characteristics, endpoint and detection rate, number of readers, sensitivity, specificity, negative (NPV) and positive predictive value (PPV) as well as accuracy. Whenever possible, sensitivity, specificity, NPV, PPV as well as 95% confidence intervals were calculated. If performance was assessed on region and patient basis, we included patient-based results.

3. Evidence Synthesis

The heterogeneity of the studies entailed that summary statistics from different studies could not be combined meta-analytically. Hence we summarized the results narratively.

3.1. Characteristics of included articles

Between 2012 and 2020, 4097 studies were identified using our search criteria (Figure 1, PRISMA flow diagram). Title and abstract screening resulted in 360 studies that entered full-text assessment. Additional 25 studies were retrieved through reference screening. After full-text assessment, 246 studies were excluded. Thus, 139 studies remained eligible for inclusion. Of these, 83 examined imaging for T, 47 for N and 24 for M staging of newly diagnosed PCa Fifteen studies reported on several endpoints, while most commonly T and N stage were combined. Thirty-three studies compared different imaging modalities. In 13 reports, imaging modalities were compared or incorporated into currently used nomograms (e.g. MSKCC/Briganti nomogram, Partin Tables). Most patient cohorts for N and M assessment consisted of intermediate and/or high-risk patients while for T staging, several studies also included low- or favorable intermediate-risk patients. Sample size varied widely, ranging from 10 to 1045 patients. Study design comprised primarily retrospective series (71%). However, 40 studies reported prospectively including one randomized controlled trial (RCT).

3.2. Quality of studies

Quality of included studies differed widely and was overall moderate (Supplementary Tables 1 – 3, Supplementary Figure 1). For T and N status risk of bias was rated lower compared to M status. Regarding patient selection, risk of bias was rated unclear in most studies, as patient enrollment was not reported. All studies for T and N staging reported on pre-selected patients, as only RP candidates were included. Index test was considered low risk of bias if readers were blinded to clinical data and reference standard results and if interpretation was done in a standardized fashion. Although many studies reported blinding, interpretation differed among readers and many lacked standardized reporting. Interpretation of reference of standard was considered at low risk of bias in case of histological confirmation and blinding to index test results. However, most studies lacked information on blinding to index test results. Therefore, risk of bias was rated unclear in most studies for T and N stage. For M status all studies were considered high risk of bias as reference standard consisted of a best value comparator using different definitions and follow-up periods. Moreover, follow-up imaging was interpreted with knowledge of index test results and therefore inevitably at high risk of bias. Flow and timing was rated unclear in most studies, as time interval between index tests and/or standard reference was not reported. Concerns of applicability were present in only few studies (Supplementary Tables 1 – 3, Supplementary Figure 1). Regarding index test and patient selection concerns of applicability was rated higher compared to reference of standard. Varying imaging techniques or interpretation by different readers without standardized reporting contributed to the higher rate of applicability concerns with respect to the index test. Regarding patient selection, some studies included only pre-selected patients and were therefore rated with high concerns of applicability.

3.3. T stage: Detection of extraprostatic extension and seminal vesicle invasion

We identified 42 studies that examined the role of imaging for extraprostatic extension (EPE), 31 for seminal vesicle invasion (SVI), and 34 for overall presence of ≥pT3 disease (Table 1a, Table 1b).^8–90 A total of 77 studies examined performance of MRI (59 mpMRI) and eleven of PSMA PET/CT or PET/MRI including five studies that compared MRI to PSMA–PET. In addition, one study compared results of mpMRI to 18F-Fluorocholine- (FCH-) PET/CT.⁶⁰ While study design was retrospective in 67 (81%), 15 studies reported prospective results. Sample size ranged widely from 21 to 1045 patients. Study populations were notably heterogeneous; however, most frequently mean/median PSA was ≤10ng/ml and Gleason score (GS) ≤7. Six studies focused on higher-risk patients.^{14, 30, 34, 39, 54, 82} Furthermore, MRI techniques, e.g. 1.5 or 3T, use of an endorectal coil, differed among studies and most studies included pre- and post-biopsy MRIs. Additionally, definition of EPE varied between studies, considering focal EPE in some, while others defined EPE as established.

Table 1a.

Studies reporting on MRI for local tumor staging in newly diagnosed prostate cancer

Author (year)	Study design	Imaging type	Tracer/sequences	No. Patients	Patient cohort	Endpoint, Event rate	Reader, Blinding	Sensitivity	Specificity	NPV	PPV	Accuracy/AUC (%)
Alessi (2019)	R, SC	mpMRI 1) PIRADS v2 2) ESUR score	1,5T, DWI, DCE, no ERC	301	46% LR 55% IR/HR	EPE 119/301, 40%	2, B	1) 99% (96/100)^## 2) 78% (64/82)^##	23% (12/29)^## 83% (89/74)^##	98% (97/100)^## 85% (91/77)^##	46% (26/59)^## 75% (60/80)^##	NR
Berger (2018)	R, SC	mpMRI PIRADS v2 (extern)	3T, NR	50	66% ISUP 2+3 46% pT2	SVI 9/50, 18%	Diff., B	75%	95%	NR	NR	NR
Billing 2015	R, SC	mpMRI (non-academic centers)	1.5 or 3T 59 DWI 57 SPCT 70 ERC	94	GS mean 7 PSA mean 12ng/ml	≥pT3 32/94, 34% SVI 17/94, 18%	Diff, B	≥pT3 30% SVI 64%	93% 93%	73% 93%	69% 64%	73 88
Bloch (2012)	R/P, SC	mpMRI	3T, DWI, DCE, ERC	108	GS 7 61% PSA mean 11 ng/ml	EPE 32/108, 30%	6, B	75% (64/83)^*	92% (95/88)^*	91% (92/90)^*	79%(77/80)^*	86
Boesen (2015)	P, SC, (No.NCT01640262)	mpMRI (PIRADS, cutoff ≥4, ESUR score)	3T, DWI, DCE, no ERC	87	IR 56%	EPE 31/87, 36% SVI 5/87, 6%	2, B	EPE 81% SVI 80/60%^*	78% 99/85%^*	68% 99/97%	88% 80/20%	79 98/84
Caglic (2019)	R, SC	mpMRI (PIRADS v2)	3T, DWI, DCE 2D vs. 3D	75	GS 7 67% PSA median 9ng/ml	EPE 48/75 64%	1, B	3D 75% 2D 65%	84% 86%	75% 68%	84% 84%	88 84
Cerantola (2013)	R, SC	mpMRI	3T, DWI, DCE, ERC	60	64% HR	EPE 31/60, 52%	2, NB	35%	90%	57%	79%	62
Chong (2014)	R, SC	mpMRI	3T, DWI	76	GS mean 7 PSA mean 9ng/ml	EPE 31/76, 41%	2, B	77%	95%	96%	73%	92
Cornud (2012)	P, SC	mpMRI	3T, DWI, DCE, ERC	178	40% LR 50% IR	EPE 38/178, 21% SVI 12/178, 7%	2, B	EPE 55/84%^** SVI 83%	96/85%^** 99%	89/99% 99%	81/51%^** 91%	NR
Counago (2014)	R, SC	mpMRI	3T, DWI, DCE, no ERC	47	34% LR 26% IR	≥T3 11/47, 23%	1, NR	57%	95%	93%	67%	89
Cybulski (2019)	P, SC	mpMRI (PIRADS v2)	1.5T, DWI, DCE	36	GS >6, ≤ 1 lesion/lobe	EPE 15/36, 43%	2, NR	80%	71%	83%	66%	NR
Davis (2016)	R, SC	mpMRI (extern community radiology centers)	3T, DWI, DCE	133	39% LR 48% IR 13% HR	EPE 32/133, 24% LR 12 % IR 28% HR 47%	Diff., B	13% (0/25)^##	93% (98/89)^##	77% (88/57)^##	33% (0/67)^##	NR
De Cobelli (2015)	R, SC	mpMRI (PIRADS v1)	1.5T, DWI, DCE, ERC	223	AS candidates, PSA mean 6ng/ml	EPE 45/223, 20% SVI 7/223, 3%	1, NR	EPE 100% SVI 100%	10% 8%	100% 100%	25% 3%	NR
Dominguez (2018)	R, SC	mpMRI (ESUR)	1.5T, DWI, DCE, no ERC	79	GS 7 59% PSA median 7ng/ml	EPE 31/79, 39% SVI 21/76, 27%	2, B	EPE 55% (54/53)^# SVI 19%	91% (77/80)^# 100%	74% (89/83)^# 76%	81% (33/48)^# 100%	76 73/73 77
Draulans (2019)	R, SC	bpMRI	1.5T, DWI	180	GS ISUP 2-3 68% PSA<10ng/ml 64%	≥pT3 80/180, 44%	4, NR	59%	69%	69%	59%	71
Falgario (2020)	R, SC	mpMRI (PIRADS v2)	3T, 61% intern 39% extern	975	23% AA vs. 77% CA	≥pT3 255/975, 26%	Diff., NR	AA: 46% CA: 46%	84% 74%	87% 78%	39% 41%	65 60
Feng (2015)	R, SC	mpMRI (PIRADS v1)	3T, DWI, DCE, no ERC	112	GS 7 42% PSA mean 8ng/ml	EPE 29/112, 26%	1, B	42/73%^** 14/73%^#	99/91% 91/91%^#	91/95% 97/95%	88/57% 6/57%	72/86
Feng (2015)	R, SC	mpMRI (PIRADS v1)	3T, DWI, DCE, no ERC	112	GS 7 42% PSA mean 8ng/ml	EPE 26/112, 23%	1, B	86%	87%	95%	67%	NR
Gaunay (2017)	R, SC	mpMRI (PIRADS, ESUR)	3T, DWI, DCE, ERC	74	NR	EPE 24/74, 32%	NR	58%	98%	82%	93%	84
Ghafoori (2015)	NR, SC	MRI	1.5T, DCE, ERC	238	GS mean 6 PSA mean 17ng/ml	SVI 63/238, 24%	1, NR	97%	98%	99%	94%	NR
Grivas (2018)	R, SC	mpMRI	3T, DWI, DCE, ERC	527	HR 59% PSA median 7ng/ml	SVI 54/527, 10%	Diff. + 1 exp., NR	76/85% ^*	95/96%^*	97/98%^*	62/70%^*	88
Gupta (2014)	R, SC	mpMRI	3T, DWI, DCE, ERC	60	GS 6 47% PSA median 5ng/ml	EPE 18/60, 30%	1, B	78%	83%	90%	67%	82
Hegde (2013)	R, SC	mpMRI	3T, DWI, DCE, ERC	118	32% LR 53% IR 15% HR	EPE 19/118, 16% SVI 10/118,8%	Diff., NR	EPE 28% SVI 50%	91% 99%	79% 96%	50% 83%	75 95
Hole (2013)	P, SC,	mpMRI	1.5T, DWI SPCT, no ERC	209	GS 7 52% PSA mean 20ng/ml	≥pT3 135/209, 65%	2, NR	66%	82%	50%	85%	65
Jäderling (2019)	P, SC	bp/mpMRI (PIRADS v1/2, ESUR score)	Mostly 1.5T, T2, DWI (47% intern, 53% extern)	557	GS 7 67% PSA median 6ng/ml	≥pT3 234/557, 42%	2, B	79%	57%	NR	NR	NR
Jäderling (2018)	R, SC	bpMRI (PIRADS v2)	3T, DWI, no ERC 2D vs. 3D	94	GS 7 70% PSA median 6ng/ml	≥pT3 39/94, 41%	2, B	3D 77/69%^* 2D 77/74%^*	43/59%^* 48/64%^*	69/68%^* 70/78%^*	53/60%^* 56/58%^*	62/65 70/68
Jambor (2018)	P, SC (NCT02002455)	PET/CT or PET/MRI, mpMRI	18F FACBC 3T, DWI, DCE	26	GS 7 77%	≥pT3 20/26, 77% (based on MRI part of PET/MRI or mpMRI)	2, B	45%	83%	31%	90%	NR
Jansen (2018)	R, MC	mpMRI (60% PIRADS v1/2)	3T, DWI, DCE, no ERC	430	GS 7 42% PSA median 9ng/ml	≥pT3 137/430, 32%	Diff, NB	45% (42/49)^##	76% (76/73)^##	75%	47%	NR
Jeong (2013)	R, SC	mpMRI	1.5 or 3T, partly DWI, ERC	922	HR	EPE 530/922, 58% SVI 117/922, 13%	4, NB	EPE 43% SVI 35%	84% 94%	52% 83%	79% 62%	61 81
Johnston (2013)	R, SC,	MRI	1.5T, no DWI, no ERC	568	35% LR 53% IR	EPE 280/568, 49% SVI 34/568, 6%	Diff., NB	EPE 20% (15/26)^## SVI 0% (0)^##	80% (70/84)^## 94% (94/95)^##	NR	NR	NR
Kam (2019)	R, SC	mpMRI (PIRADS v1/2, 3 centers)	1.5-3T	235	ISUP 2-3 76% PSA mean 9ng/ml	≥pT3 132, 56%	Diff., B	38%	95%	57%	90%	NR
Kan (2014)	R, SC	MRI	1.5T, DWI	subgroup of 56 with MRI	PSA <10ng/ml 64%	≥pT3 17/56, 30.4%	Diff., NR	6%	95%	70%	33%	68
Kayat Bittencourt (2015)	R, SC	mpMRI (PIRADS, ESUR)	3T, DWI, DCE, 89 with ERC	133	GS ≥7 87% PSA median 9ng/ml	≥pT3 60/133, 45%	1, NB	55 −80%	51-73%	66-77%	57-64%	64-74
Kim (2012)	R, SC	MRI	3T ERC/PAC	151 63 ERC 88 PAC	GS 6 appr. 56% PSA mean 12ng/ml	EPE 81/151, 54% SVI 34/151, 23%	2, NR	EPE 33/ 31% SVI 46/43%	97/98% 92/93%	57/54% 87/84%%	92/94% 60/64%	64/61 83/81
Kongnyuy (2017)	R, SC	mpMRI	3T, DWI, DCE	379	mostly GS 6+7	≥pT3 87/379, 23%	2, NR	56%	72%	85%	37%	71
Kozikowski (2018)	P, SC	mpMRI	3T, DWI, DCE	154	18% LR 37% IR vs. 46% HR	≥pT3 49/ 154, 31.8%	1, NB	41% (20/50)^##	93% (96/89)^##	77% (85/65)^##	74% (50/81)^##	76 82/70^##
Lawrence (2014)	P, SC	MRI	3T, DWI	40	IR/HR	≥pT3 23/40, 58% 38/136 regions, 28% per region analyses	2, B	44/ 82%^*	83/66%^*	75/88%^*	57/55%^*	67/82^*
Lebacle (2017)	R, SC	MRI	Extern, no restrictions	853	GS 6 57% PSA mean 10ng/ml	EPE 329/853, 31%	diff, NR	35%	86%	64%	65%	NR
Lee (2017)	R, SC	mpMRI	1.5-3T, DWI, no ERC	1045	GS 6 48% PSA median 6ng/ml	EPE 314/1045, 27% SVI 80/1045, 7%	2, B	EPE 55% SVI 44%	81% 95%	NR	NR	NR
Lim (2017)	R, SC	mpMRI (PIRADS v2, ESUR)	3T, DWI, DCE, no ERC	113 with PIRADS score ≥4	GS 7 79%	≥pT3 76/113, 67%	2, B	49%	87%	NR	NR	68/59^*
Martini (2018)	R, SC	mpMRI (61% in-, 39% extern)	3T, DWI, DCE,	561, 829 lobes	ISUP 1+2 69.3% PSA median 6ng/ml	EPE 142/829, 17% per lobes	Diff., B	40%	92%	88%	50%	69
Martini (2019)	R, SC	mpMRI (PIRADS v2)	NR	291	cT1-2N0	EPE 35/291, 12%	NR	43%	95%	NR	NR	NR
Matsuoka (2017)	R, SC	mpMRI PIRADS 1) v1 vs. 2) v2	1.5T, DWI, 160 DCE	210	GS 7 51% PSA 7ng/ml	EPE 56/210, 27%	2, B	1) 55/73%^* 2) 93/ 95%^*	92-80%^* 67/64%^*	85-89%^* 96/97%^*	71-57%^* 51/49%^*
Muehlematter (2019)	R, SC	mpMRI (29 in-, 11 extern)	1.5-3T, if intern T2, DWI, DCE	40	20% IR 80% HR	EPE 12/40, 30% SVI 5/40, 13%	4, B	EPE 46% SVI 35%	75% 98%	NR	NR	66 65
Nandukar (2019)	R, SC	mpMRI	NR	112	NR	SVI, NR	Diff., NR	30%	99%	NR	NR	NR
Nepple (2013)	R, SC	MRI	1.5T, ERC	91	HR	EPE 22/91, 24% SVI 8/91, 9%	Diff., NR	EPE 55% SVI 38%	64% 99%	81% 94%	32% 75%	62 93
Oon (2015)	R, SC	MRI, incl. 37mp	1.5T, DWI, DCE, no ERC	88	PSA mean 9ng/ml	EPE 12/88, 14% SVI 7/88, 8%	5, NR	EPE 75% SVI 17%	100% 100%	96% 91%	100% 100%	NR
Otto (2014)	R, SC	mpMRI	3T, T1, T2, DWI, DCE, spect. ERC	37	GS 7 51%	EPE 10/37, 27% SVI 5/37, 14%	2, B	EPE 90/80%^* SVI 80/100%	74/82%^* 96/99%	NR	NR	78/81^* 95/97
Park (2014)	R, SC	mpMRI	3T, DWI, DCE	353	44% LR 37% IR 19% HR	≥T3 21/157, 13% 50/129, 39% 40/67, 60%	2, B	56% LR 33% IR 46% HR 80%	82% 90% 68% 85%	80% 90% 67% 74%	59% 33% 48% 89%	74 82 60 82
Pinaquy (2015)	R, SC	mpMRI	1.5T, DWI, DCE, ERC	47	HR	EPE 25/47, 53% SVI 8/47, 17% Per sextant	1,B	EPE 72% SVI 73%	77% 95%	59% 73%	86% 95%	NR
Porcaro (2013)	R, SC	MRI	1.5T, ERC	154	GS mean 6 PSA mean 11ng/ml	EPE 41/154, 27% SVI 16/154, 10%	2, B	EPE 78% SVI 88%	96% 98%	92% 99%	86% 82%	91 97
Radtke (2015)	R, SC	mpMRI (PIRADS, ESUR score)	3T, T2, DWI, DCE, no ERC	132	18 LR 79 IR 35 HR	≥pT3 57/132, 43%	2, B	LR 50% IR 58% HR 67%	81% 96% 82%	93% 78% 53%	25% 90% 89%	82
Raeside (2019)	R, SC	mpMRI (PIRADS v2)	1.5/3T 1) T2 2) 1)+DWI 3) 2)+DCE 4) 3 + PIRADS	245 1) 100 2) 43 3) 52 4) 50	1) GS 7 80% 2) GS 7 74% 3) GS 7 85% 4) GS 7 59%	≥pT3 1) 48/100, 48% 2) 26/43, 60% 3) 32/52, 62% 4) 32/50, 60%	Diff., NR	1) 27% 2) 23% 3) 38% 4) 63%	90% 94% 80% 71%	NR	NR	NR
Raskolnikov (2015)	P, SC	mpMRI	3T, DWI, DCE, SPCT, ERC	169	NR	EPE 39/169, 23%	2, B	49%	74%	83%	36%	NR
Renard-Penna (2013)	P, SC	MRI	1.5T, DCE, no ERC	101	Mean PSA 8ng/ml	≥pT3 16/101, 16%	2, B	81/44%^*	94/92%	96/90%	72/50%	90/69
Roethke (2013)	R, SC	MRI	1.5T, ERC	385	PSA mean 9ng/ml	≥pT3 103/385, 27%	2, NR	42% (20/48)^##	92% (94/94)^##	78% (96/68)^##	69% (14/87%)^##	NR
Roethke (2014)	R, SC	MRI	1.5T, ERC	376	GS median 7 PSA mean 9ng/ml	SVI 35/376, 9%	2, NR	49%	98%	95%	68%	93
Rosenkrantz (2012)	R, SC	mpMRI	3T, DWI, DCE, no ERC	51	NR	EPE 24/51, 47%	2, B	R1 71-79%^* R2 29-71%^*	62-77% 58-92%	86-89% 77-86%	44-54% 38-57%	67-76 61-75
Rosenkrantz (2016)	R, SC	mpMRI	3T, DWI 1) irregularity 2) LCC	90, 180 lobes	PSA mean 9ng/ml	≥pT3 40/90, 44% 46/180 lobes, 26% per lobe	2, B	1) 63/75%^* 2) 80/89%^*	81%^* 75/73%^*	NR	NR	NR
Rud (2015)	P, SC (MRI arm of NCT01347320)	mpMRI	1.5T, DWI	199	26% LR 51% IR 23% HR	≥pT3 105/199, 53%	1, half-B	72% (68/86)^##	65% (67/71)^##	68% (75/75)^##	70% (60/83)^##	69%
Ruprecht (2012)	R, SC	MRI	1.5T, ECR	46	NR	≥pT3 18/46, 39%	2, B	EPE 78/33%^*	93/71%^*	87/63%^*	88/43%^*	87 57
Sauer (2018)	R, SC	mpMRI (PIRADS v2)	3T, DWI DCE	198, 396 lobes	PSA median 5ng/ml	≥pT3 87/198, 44% 1) ≥pT3 2) NVBI 3) NVBI based on PIRADS ≥4	2, NB	1) 64% 2) 75% 3) 84%	89% 94% 39%	76% 92% 88%	82% 80% 31%	78 89 50
Schieda (2015)	R, SC	mpMRI 1) PIRADS, ESUR 2) no PIRADS	3T, DWI, DCE	145 1) 80 no PIRADS 2) 65 PIRADS	GS 7/8 82% PSA 9ng/ml	≥pT3 1) 53/80, 66% 2) 42/65, 65%	7, NR	1) 25% 2) 60%	75% 68%	NR	NR	42 63
Sharif-Afshar (2015)	R, SC	mpMRI, (analog PIRADS, ESUR)	3T, DWI, DCE, no ERC	101	GS 6+7 85% PSA mean 9ng/ml	EPE 25/101, 25%	1, NB	79%	89%	92%	73%	NR
Somford (2013)	P, SC	mpMRI	3T, T2, DWI, DCE, ERC	183	40% LR 34% IR 26% HR	≥pT3 91/183, 50% 18/73, 25% 36/62, 58% 37/48, 77%	2, NB	All 58% LR 61% IR 50% HR 65%	89% 91% 92% 73%	68% 88% 57% 38%	84% 69% 90% 89%	74
Tanaka (2013)	P, SC	MRI	3T, DWI, DCE, no ERC	67	GS 7 45% PSA median 7ng/ml	≥pT3 17/67, 25% 20/134, 15% sides per sides	1, NR	60%	86%	93%	43%
Tay (2016)	R, SC	mpMRI	3T, DWI, DCE	120	GS 6+7 77% PSA median 5ng/ml	EPE 56/120, 47%	Diff. vs. 1, B	86/77%^*	81/44%^*	NR	NR	83/59^*
Toner (2017)	R, MC	mpMRI 1) PIRADS ≥3 2) PIRADS ≥4 3) MRI EPE	Most 3T, DWI, DCE (extern)	152	PSA median 6ng/ml	≥pT3 68/152, 45% 1) 10/24, 42% 2) 19/51, 37% 3) NR	Diff. (extern), NB	1) 85% 2) 71% 3) 29%	27% 44% 94%	70% 65% 62%	49% 51% 80%	56 57 62
Tsao (2013)	R, SC	MRI	1.5T, CE, ERC	94	NR	EPE 12/94, 13% SVI 17/94, 18%	NR	EPE 25% SVI 35%	71% 96%	NR	NR	68 85
Van Holsbeeck (2016)	R, SC	mpMRI	1.5T, DWI, no ERC	123	GS 7 60% PSA mean 11ng/ml	EPE 61/123, 50% SVI 28/123, 23%	3, NR	EPE 57/85%^** SVI 54%	92/84%^** 99%	67/85%^** 88%	87/84%^** 94%	75/85^** 89
Van Leeuwen (2019)	R, MC	mpMRI (PIRADS, ESUR)	1.5/3T, DWI, DCE	140	21% IR 79% HR	SVI 43/140, 31%	Diff., B	65%	95%	85%	86%	NR
Wang (2014)	R, SC	mpMRI	3T, DWI, DCE	25	HR	≥pT3 17/25, 68%	2, NR	77%	71%	60%	87%	NR
Wibmer (2014)	R, SC	mpMRI	1.5/3T, DWI, DCE, ERC	211	GS 7 68% PSA median 7ng/ml	≥pT3 72/211, 34%	3, NR	31/65%^**	96/90%^**	72/83%^**	79/77%^**	85
Xylinas (2013)	R, SC	MRI	1.5T, DCE, no ERC	70 cT3 in DRE	GS ≤7 94% PSA mean 11ng/ml	≥pT3 57/81, 81%	1, B	95%	69%	75%	93%	87
Yilmaz (2019)	R, SC	mpMRI (PIRADS v2)	3T, DWI, DCE	24	13% LR 62% IR 25% HR	EPE 10/24, 42% SVI 4/24, 17%	1, B	EPE 90% SVI 100%	86% 95%	92% 100%	82% 80%	88 96
Zanelli (2019)	P, SC	mpMRI (PIRADS v2)	3T, DWI, DCE	73	ISUP 1+2 86% PSA median 7ng/ml	≥pT3 24/73, 33%	3, B	63/67/58%^*	82/74/88%^*	NR	NR	73/75/74
Zapala (2019)	R, SC	mpMRI (PIRADS, ESUR)	1.5T, DWI, DCE, ERC	88	GS ≤6 47% PSA<10 70%	EPE 41/88, 47%	1, NB	42%	88%	78%	60%	65

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Abbreviations:

NPV negative predictive value

PPV positive predictive value

AUC Area under the ROC curve

R retrospective

P prospective

SC single center

MC multicenter

mp/bp MRI multiparametric/biparametric magnetic resonance imaging

PIRADS Prostate Imaging Reporting and Data System

ESUR European Society of Urogenital Radiology

DWI diffusion weighted imaging

DCE dynamic contrast enhanced

ERC endorectal coil

PAC pelvic phased-array coil

SPCT spectroscopy

LCC length of capsular contact

DRE digital rectal examination

LR, IR, HR low-, intermediate-, high-risk patients

GS Gleason score

PSA prostate specific antigen

≥pT3 overall extraprostatic extension

EPE extraprostatic/-capsular extension

SVI seminal vesicle invasion, pT3b

B blinded

NB not blinded

NR not reported

among different readers (exp/less exp)

^**

definitive/suspicious in MRI

focal/established ECE

^##

within diff risk groups

Table 1b.

Studies reporting on PET/CT and comparison of PET/CT to MRI for local tumor staging in newly diagnosed prostate cancer

Author (year)	Study design	Imaging type	Tracer/sequences	No. Patients	Patient cohort	Endpoint, Event rate	Reader, Blinding	Sensitivity	Specificity	NPV	PPV	Accuracy/AUC (%)
Berger (2018)	R, SC	1) PET/CT 2) mpMRI PIRADS v2 (extern)	68Ga- PSMA 3T, NR	50	66% ISUP 2+3 46% pT2	SVI 9/50, 18%	1) 1 2) Diff., B	1) 11% 2) 75%	93% 95%	NR	NR	NR
Dekalo (2019)	R, SC	PET/CT	68Ga- PSMA	59	51% IR 49% HR	EPE 17/59, 29% SVI 10/59, 21%	Diff, B	EPE / (0/17) SVI 58%	100% 96%	71% 90%	/ 78%	NR 77
Fendler (2016)	R, SC	PET/CT	68Ga PSMA	21	IR + HR	EPE 12/21, 57% SVI 11/21, 52%	2, B	EPE 50% SVI 73%	100% 100%	60% 77%	100% 100%	71 86
Grubmuller (2018)	P, SC, (NCT02659527)	PET/mpMRI (PIRADS)	68Ga PSMA 3T	80	GS 7 49% PSA median 8ng/ml	EPE 21/80, 26% SVI 18/80, 23%	2, NR	EPE 67% SVI 94%	92% 95%	89% 98%	73% 84%	79 94
Gupta (2018)	R, SC	PET/CT	68Ga PSMA	Subgroup 23	PSA ≥20ng/ml 70%	≥pT3 19/23, 83% SVI 14/23, 61%	2, B	≥pT3 63% SVI 55%	100% 100%	36% 25%	100% 100%	NR
Muehlematter (2019)	R, SC	1) PET/CT 2) mpMRI (29 in-, 11 extern)	68Ga PSMA 1.5-3T, if intern T2, DWI, DCE	40	20% IR 80% HR	EPE 12/40, 30% SVI 5/40, 13%	4, B	EPE1) 69% EPE2) 46% SVI1) 55% SVI2) 35%	67% 75% 94% 98%	NR	NR	73 66 79 65
Nandukar (2019)	R, SC	1) PET/CT 2) mpMRI	68Ga PSMA NR	142, 112 MRI	NR	SVI 37/142 26%	Diff., NR	1) 47% 2) 30%	87% 99%	NR	NR	NR
Pinaquy (2015)	R, SC	1) PET/CT 2) mpMRI	18F-FCH 1.5T, DWI, DCE, ERC	47	HR	EPE 25/47, 53% SVI 8/47, 17% Per sextant	1) 1 2) 1, B	EPE1) 76% EPE2) 72% SVI1) 36% SVI2) 73%	77% 77% 98% 95%	63% 59% 90% 73%	86% 86% 80% 95%	NR
Thalgott (2018)	R, SC	PET/MRI (mpMRI)	68Ga PSMA	73	HR	EPE 53/73, 73% SVI 33/73, 45%	1, B	EPE 94% SVI 82%	45% 80%	75% 84%	82% 77 %	70 81
Van Leeuwen (2019)	R, MC	1) PET/CT 2) mpMRI (PIRADS, ESUR)	68Ga PSMA 1.5/3T, DWI, DCE	140	21% IR 79% HR	SVI 43/140, 31%	Diff., B	1) 46% 2) 65%	93% 95%	80% 85%	74% 86%	NR
Von Klot (2017)	R, SC	PET/CT	68Ga PSMA	21	GS median 7 PSA mean 11.9ng/ml	EPE 6/21, 29% SVI 4/21, 19%	2, B	EPE 90% SVI 75%	91% 100%	91% 97%	90% 100%	NR
Yilmaz (2019)	R, SC	1) PET/CT 2) mpMRI (PIRADS v2)	68Ga PSMA 3T, DWI, DCE	24	13% LR 62% IR 25% HR	EPE 10/24, 42% SVI 4/24, 17%	1) 2 2) 1, B	EPE1) 30% EPE2) 90% SVI1) 75% SVI2) 100%	93% 86% 90% 95%	65% 92% 95% 100%	75% 82% 60% 80%	67 88 88 96

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Abbreviations:

NPV negative predictive value

PPV positive predictive value

AUC Area under the ROC curve

R retrospective

P prospective

SC single center

MC multicenter

mpMRI multiparametric magnetic resonance imaging

PIRADS Prostate Imaging Reporting and Data System

ESUR European Society of Urogenital Radiology

DWI diffusion weighted imaging

DCE dynamic contrast enhanced

ERC endorectal coil

PET/CT positron emission tomography/computed tomography

PSMA prostate specific membrane antigen

18F-FCH 18F-Fluorocholine

LR, IR, HR low-, intermediate-, high-risk patients

GS Gleason score

PSA prostate specific antigen

≥pT3 overall extraprostatic extension

EPE extraprostatic/-capsular extension

SVI seminal vesicle invasion, pT3b

B blinded

NR not reported

3.3.1. mpMRI

Current guidelines recommend mpMRI, which combines morphological T2 weighted with functional imaging sequences for pre-biopsy assessment.¹ A remarkable number of studies examined the role of MRI in the context of local T staging (Table 1a). Sample size and event rate among included studies and thus confidence intervals differed widely. Therefore sensitivity varied enormously (0 – 100%) between different studies on MRI for detection of EPE and/or SVI. However, some findings are worth reporting in more detail. The largest series to date was published by Lee et al., including 1045 patients, 314 (27%) with EPE, who underwent mpMRI before RP at a single institution.⁴⁹ Although mpMRI were reviewed by only two experienced radiologists, blinded to all clinical data, sensitivity and specificity in this retrospective study remained relatively low (53% and 82%). It is of note that different MRI techniques (1.5-3T) and no standardized reporting were used. Moreover, most patients had GS 6 (48%) or 7 (36%) and median PSA was 6.1ng/ml, representing a lower risk cohort with presumably lower rates of EPE.

3.3.1.1. Risk-stratification

Several studies thought to assess performance of MRI according to different risk groups.^{8, 19, 20, 24, 38, 40, 46, 59, 62, 66, 70, 75} While better performance for high-risk patients has been presumed in literature, the data actually remain inconclusive. For example, Jeong et al. analyzed 922 high-risk patients, 530 (58%) with EPE and 117 (13%) with SVI, undergoing 1.5-3T mpMRI and reported sensitivity for EPE and SVI of 43% and 35%.³⁹ MRIs included only partly diffusion-weighted imaging and no standardized reporting was used. Moreover, Jansen et al. observed comparable sensitivity for prediction of EPE between 133 high-risk and 297 low-risk patients (49% vs. 42%, p=0.5).³⁸ In this study, mpMRIs were evaluated by different radiologists applying standardized reporting in approximately 60% of cases. Using PIRADSv2, Alessi et al. reported considerably high overall sensitivity of 99% and a small but statistically not significant increase between 137 low- and 164 intermediate/high-risk patients (96% vs. 100%).⁸ Falagario et al. reported on 975 African and Caucasian American (CA) men undergoing preoperative mpMRI.²⁴ Stage ≥pT3 was noted in 255 patients (26%). While there was no difference with respect to race, sensitivity of MRI was lower for low-risk compared to high-risk Caucasian Americans (28% vs. 58%).

3.3.1.2. Reader experience

Interpretation of mpMRI might vary between different readers with an assumed benefit for radiologists with high level of MRI experience.^{12, 30, 58, 65, 71, 73, 77} Though several studies reported better performance among radiologists with high level of experience, most had only small sample sizes with wide and overlapping confidence intervals. Using logistic regression models, Tay et al. observed only small incremental benefit of mpMRI over clinical parameters when standard radiological reports were considered.⁷⁷ However, EPE classification increased significantly by adding a specialized report of a dedicated expert in prostate mpMRI (AUC 0.91 vs. 0.69, p<0.001). At closer examination, this difference was due to improvements in specificity (44% vs. 81%) while sensitivity remained comparable (77% vs. 86%). Moreover, Schieda et al. found better sensitivity and accuracy for EPE among experienced radiologists when no standardized reporting was used among a small cohort of 145 men (see 3.3.1.3).⁷³

3.3.1.3. Standardized reporting

To overcome variability due to subjective interpretation, the ESUR has introduced a standardized reporting system for mpMRI (PIRADSv2, ESUR EPE score). For example, Schieda et al. analyzed performance of mpMRI for predicting EPE with respect to the use of PIRADS classification.⁷³ While the authors observed significantly better sensitivity and accuracy among experienced radiologists without the use of standardized reporting, interestingly, this difference disappeared when PIRADS was applied. Furthermore, overall accuracy increased with the use of PIRADS (42% vs. 63%, p=0.006). However, sample size was relatively small. Kam et al. observed significant improvement in sensitivity for prediction of EPE (30% to 60%) when applying PIRADS v2 compared to v1 in 235 patients. However, this study lacked information on patient characteristics, MRI findings, event rate, confidence intervals or further outcomes for the different groups. Overall, interobserver agreement was poor to moderate in most studies and moderate to good for studies using PIRADS v2.^{36, 50, 53, 58, 65, 71, 72}

3.3.1.4. Setting

Four studies examined performance of MRI when performed and interpreted in non-academic settings.^{10, 19, 48, 52} Davis et al. assessed performance of mpMRI performed in community centers among 133 patients and reported sensitivity of 0% in a subgroup of 52 low-risk patients.¹⁹ Lebacle et al. showed sensitivity of 35% in a cohort of 853 patients that underwent MRI externally without any restrictions.⁴⁸ However, up to date no studies directly compared quality and performance of MRIs performed in academic vs. non-academic settings.

3.3.1.5. Other

Another approach to increase sensitivity, usually at a cost of specificity, consists of combination of indirect and direct MRI signs of EPE, although studies remain too small for firm conclusions to be drawn.^{16, 26, 56, 81, 85} Moreover, several MRI factors other than direct indications of EPE have been proposed such as tumor contact length, tumor diameter, primary lesion score or size.^{28, 45, 50, 69, 89} To date, no external validation of these factors has been conducted.

3.3.2. PSMA-PET

PSMA-PET/CT has already demonstrated its value in the context of recurrent PCa.⁵ For staging at diagnosis, most studies included intermediate- or high-risk patients. In these, PSMA-PET/CT or PET/MRI offers the advantage of whole body imaging combined with local staging, which might result in lower costs and time saving, than pelvic MRI. Eleven studies reported on the use of 68Ga-PSMA PET/CT or PET/MRI for local tumor staging of primary PCa and reported mixed results (Table 1b). Most studies included only small patient cohorts or had few events, inherent with high level of uncertainty, resulting in a wide range of reported sensitivity (0-94% for EPE; 11-94% for SVI).^{9, 21, 25, 31, 32, 54, 55, 78, 82, 83, 87} Thalgott et al. assessed PSMA-PET/mpMRI for T staging in 73 high-risk patients, including 53 (71%) with EPE as well as 33 (45%) with SVI and found high sensitivity of 94% for prediction of EPE and 83% for SVI.⁷⁸ In contrast, Van Leeuwen et al. reported sensitivity of 46% for SVI analyzing 140 men including 43 (31%) with SVI.⁸² Dekalo et al. assessed 59 intermediate- and high-risk patients and observed sensitivity of 58% for SVI while PSMA-PET/CT detected none out of 17 patients with EPE.²¹

3.3.3. Comparisons and clinical risk tools

A comparison or incorporation into commonly used clinical risk stratification tools such as the Partin Tables and the MSKCC nomogram that rely on clinical parameters and biopsy results was performed in ten studies. ^{19, 21, 23, 27, 30, 33, 45, 78, 88, 89} All but two reported better performance for imaging (mostly MRI) although external validation is pending.^{19, 21, 23, 27, 30, 33, 45, 78, 88, 89} Highest accuracy was achieved when imaging was incorporated into existing models. For example, Gupta et al. observed AUC of 0.82 vs. 0.62 for a model using mpMRI to predict EPE compared to Partin Tables.³³ Thalgott et al. reported superior sensitivity for PSMA PET/MRI over MSKCC nomogram or Partin tables for prediction of EPE (94% vs. 66% vs. 71%).⁷⁸ However, accuracy did not differ. Incorporating mpMRI into Partin Tables, AUC of 0.93 was reported, incorporating mpMRI into MSKCC, AUC of 0.95 was achieved.²⁷ Similar gain in AUC was observed for incorporation of PSMA-PET into the MSKCC nomogram (0.84 to 0.91).²¹

Five studies thought to compare mpMRI to PSMA-PET/CT (Table 1b).^{9, 54, 55} However, none of them could demonstrate significant superiority of one modality to another.

3.4. N stage: Detection of lymph node metastases

Similar to T staging, due to widely heterogeneous studies, we found a wide range of sensitivity and specificity from 10 – 100% and from 33 –100% (Table 2a, Table 2b). A total of 17 studies were prospective, while 30 reported retrospective results. Most studies relied on intermediate- or high-risk patients and 13 compared different imaging modalities.

Table 2a.

Studies reporting on PET/CT for lymph node staging in newly diagnosed prostate cancer

Author (year)	Study design	Imaging type	Tracer/sequences	No. patients	Patient cohort	No. nodes dissected pp, event rate	Reader, Blinding	Sensitivity	Specificity	NPV	PPV	Accuracy/AUC (%)
Berger (2018)	R, SC	PET/CT	68Ga PSMA	50	66% ISUP 2+3 46% pT2	Median 12 2/50, 4%	1, B	50%	92%	98%	20%	NR
Budäus (2016)	R, SC	PET/CT	68Ga PSMA	30	Briganti risk >20%	Median 19 12/30, 40%	Diff., B	33%	100%	69%	100%	73
Cytawa (2020)	R, SC	PET/CT	68Ga PSMA	Subgroup 40 270 LN regions	50% IR 50% HR	20/270, 7% per region	3, NR	35%	98%	95%	64%	93%
Dekalo (2019)	R, SC	PET/CT	68Ga PSMA	59	51% IR 49% HR	3/59, 5%	Diff, B	67%	98%	67%	98%	82
Ferraro (2020)	R, SC	PET/CT	68Ga PSMA	60	13% IR 87% HR	Median 21 12/60, 20%	2, NB	58%	98%	90%	88%
Grubmuller (2018)	P, SC, (NCT02659527)	PET/mpMRI, followed by WB-MRI (PIRADS)	68Ga PSMA 3T	80	GS 7 49% PSA median 8ng/ml	Median 11 16/80, 14%	2, NR	69%	100%	92%	100%	93
Gupta (2017)	R, SC	PET/CT	68Ga PSMA	12	HR	7/12, 58%	2, B	100%	80%	100%	88%	92
Gupta (2018)	R, SC	PET/CT	68Ga PSMA	Subgroup 23	PSA ≥20ng/ml 70%	Mean 20 9/23, 39%	2, B	78% (53/76)^*	93% (100/99)^*	87% (97/98)^*	88% (89/87)^*	NR
Herlemann (2016)	R, SC	PET/CT	68Ga PSMA	Subgroup 20 40 LN regions	20% IR 80% HR	Mean 20 Per region 14/40, 35%	2, NR	86%	88%	92%	80%	88
Kopp (2020)	R, SC	PET/CT	68Ga PSMA	90	IR/HR	Median 13 16/90, 18%	1, B	44%	96%	70%	89%	NR
Kulkarni (2020)	R, SC	PET/CT	68Ga PSMA	Subgroup 35	IR/HR	Mean 19 16/35, 46%	1, B	81%	84%	84%	81%	83
Maurer (2016)	R, SC	PET/CT or PET/MRI	68Ga PSMA	130	23% IR 68% HR	Median 21 41/130, 32%	1, B	66%	99%	86%	96%	89
Obek (2017)	R, MC	PET/CT	68Ga PSMA	51/37 ≥15LN removed	HR	Median 19 15/51, 30%	2, B	53/67%^#	86/88%	81/85%	62/73%	76/81
Petersen (2019)	P, SC	PET/CT	68Ga PSMA	20	5% IR 95% HR	Median 23 13/20, 65%	2, B	39%	100%	47%	100%	60
Rahman (2019)	R, SC	PET/CT	68Ga PSMA	Subgroup 28	HR	0/28, 0%	2, B	/	96%	100%		NR
Thalgott (2018)	R, SC	PET/MRI	68Ga PSMA	73	HR	25/73, 34%	1, B	60%	100%	83%	100%	80
Uprimny (2017)	R, SC	PET/CT	68Ga PSMA	49	NR	18/49, 37%	2, NB	61%	90%	85	81	NR
Van Kalmthout (2020)	P, SC	PET/CT	68Ga PSMA	97 (risk on MSKCC >10%)	IR/HR	41/97, 42.3%	NR	42%	91%	68%	77%	NR
Van Leeuwen (2017)	P, SC	PET/CT	68Ga PSMA	30 (risk on Briganti >5%)	10% IR 90% HR	Median 16 11/30, 37%	2, NR	64%	95%	82%	88%
Van Leeuwen (2019)	R, SC	PET/CT	68Ga PSMA	140	21% IR 79% HR	Median 16 51/140, 36%	Diff, B	53%	88%	76%	71%	NR
Yaxley (2019)	R, SC	PET/CT	68Ga PSMA	208	41% IR 59% HR	Median 13 55/208, 26%	Diff., NR	38% (55/34%)^*	94% (96/91%)^*	81% (93/71%)^*	68% (67/78%)^*	66 (75/63)^*
Yilmaz (2019)	R, SC	PET/CT	68Ga PSMA	Subgroup 10	NR	Median NR 2/10, 20%	2, B	100%	100%	100%	100%	100
Zhang (2017)	R, SC	PET/CT	68Ga PSMA	42	40% IR 60% HR	Mean 7 15/42, 36%	3, B	93%	96%	96%	93%	NR
Kaufmann (2020)	P, SC	PET/MRI	1) 68Ga-PSMA or 2) 11C-choline	Subgroup of 24, 12 each group	HR	Median 25 5/24, 21% 1) 2/12 2) 3/12	4, B	1) 50% 2) 33%	100% 100%	91% 82%	100% 100%	91 83
Vag (2014)	P, SC	PET/CT	11C-choline	34, 76 regions	IR/HR	Per region 33/76	2, NR	70%	91%	NR	NR	83
Van den Bergh (2015)	P, SC	PET/CT	11C- choline	75, risk on Partin tables ≥10+<35% and cN0 on cCT	GS 7+8 81% PSA median 10ng/ml	Median 21 37/75, 49%	1, B	19%	90%	53%	64%	55
Heck (2014)	P, SC	PET/CT	11C-choline	33	12% IR 88% HR	Median 30 14/33, 42%	1, B	57%	90%	74%	80%	76
Schiavina (2018)	R, SC	PET/CT	11C-choline	262	41% IR 48% HR 11% VHR	Median 15 10/107 IR, 9% 38/155 HR, 25%	Team, B	IR 10% HR 50% VHR 71%	76% 76% 93%	76% 82% 76%	4% 40% 91%	44 64 86
Daouacher (2016)	P, SC	PET/CT	11C-acetate	53	11% IR, 89% HR >20% risk at Briganti	Mean 18 26/53, 49%	2, B	38%	96%	62%	91%	68
Haseebuddin (2013)	P, SC (part of 10.1007/s00259-013-2634-1)	PET/CT	11C-acetate	102	IR/HR	21/102, 21%	2, NB	68%	78%	89%	49%	NR
Schumacher (2015)	P, SC	PET/CT	11C-acetate	Subgroup 9	PSA 40ng/ml	Mean 26 4/9, 44%	1, B	75%	100%	83%	100%	NR
Gauvin (2019)	R, SC	PET/CT	18F-FCH	Subgroup 26	HR	NR	1, NR	10%	100%	64%	100%	NR
Kjoljhede (2014)	R, SC	PET/CT	18F-FCH	112	HR, normal/inconclusive BS	Median 12 48/112, 43%	2, B	33%	92%	65%	76%	NR
Mortensen (2019)	P, SC, NCT02232685	PET/CT	18F-FCH	Subgroup 80		Median 16 24/80, 30%	2, NR	63%	70%	81%	47%	68
Poulsen (2012)	P, SC NCT00670527	PET/CT	18F-FCH	210	36% IR 64% HR	Median 5 41/210, 20%	2, B	73%	88%	93%	59%	NR
Pinquay (2015)	R, SC	PET/CT	18F-FCH	47	HR	Mean 11 9/47, 19%	1, B	78%	94%	94%	78%	NR
Jambor (2018)	P, SC (NCT02002455)	PET/CT or PET/MRI	18F FACBC 3T, DWI	26	GS 7 77%	Median 16 7/26, 27%	2, B	14%	100%	76%	100%	NR
Suzuki (2019)	P, MC	PET/CT	18F FACBC	28 with LN ≥5 + <10mm	GS ≥8 55% PSA median 13ng/ml	7/28, 25%	2, B	67%	86%	91%	57%	82
Selnaes (2018)	P, SC NCT02076503	PET/MRI	18F FACBC	26	HR	Median 20 10/26, 38%	2, B	40%	100%	73%	100%	77

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Abbreviations:

pp per patient

NPV negative predictive value

PPV positive predictive value

AUC Area under the ROC curve

R retrospective

P prospective

SC single center

MC multicenter

LN lymph nodes

MRI magnetic resonance imaging

DWI diffusion weighted imaging

PET/CT positron emission tomography/computed tomography

PSMA prostate specific membrane antigen

18F-FCH 18F-Fluorocholine

18F FACBC 18F-Fluciclovine

cCT contrast enhanced computed tomography

BS bone scintigraphy

ISUP International Society of Urological Pathology

LR, IR, (V)HR low-, intermediate-, (very) high-risk patients

GS Gleason score

PSA prostate specific antigen

B blinded

NB not blinded

NR not reported

Intermediate/high risk

overall/only pat. With ≥15 nodes removed

Table 2b.

Studies reporting on MRI and comparison of MRI to PET/CT for lymph node staging in newly diagnosed prostate cancer

Author (year)	Study design	Imaging type	Tracer/sequences	No. patients	Patient cohort	No. nodes dissected pp, event rate	Reader, Blinding	Sensitivity	Specificity	NPV	PPV	Accuracy/AUC (%)
Brembilla (2018)	R, SC	mpMRI (PIRADS, ESUR)	1,5T, DWI, DCE	101, risk on Briganti >5%	GS 7 60% PSA median 11ng/ml	Median 20 23/101, 23%	2, B	17/30%^**	97/95%^**	80/82%^**	67/64%^**	57/63^**
Dominguez (2018)	R, SC	mpMRI (PIRADS, ESUS)	1.5T, DWI, DCE, no ERC	79	GS 7 59% PSA median 7ng/ml	10/79, 13%	2, B	20%	98%	87%	67%	87
Jeong (2013)	R, SC	MRI	1.5-3T, partly DWI, ERC	922	HR	58/922, 6%	4, HB	14%	97%	95%	23%	92
Shen (2018)	R, SC	MRI	3T, DWI, DCE, ERC	40	HR	13/40, 33%	2, B	46%	100%	79%	100%	NR
Vallini (2016)	R, SC	MRI	3T, DWI	26, 212 LN stations	IR/HR	Mean 17 Per station 21/212, 10%	2, B	85%	90%	97%	58%	89
Von Below (2016)	P, SC	MRI	3T, DWI	40, risk on Briganti >20%	IR/HR	Mean 18 20/40, 50%	1, NB	55%	90%	67%	85%	73
Zugor (2018)	R, 2C	MRI	1.5T, ERC	168	HR	18/168, 11%	NR	96%	33%	NR	NR	65
Gupta (2017)	R, SC	1) PET/CT 2) MRI	68Ga PSMA 1.5T, DWI	12	HR	7/12, 58%	2, B	1) 100% 2) 57%	80% 80%	100% 57%	88% 80%	92 67
Kulkarni (2020)	R, SC	1) PET/CT 2) mpMRI	68Ga PSMA 3T, DWI, DCE	Subgroup 35	IR/HR	Mean 19 16/35, 46%	1) 1, B 2) NR	1) 81% 2) 44%	84% 79%	84% 64%	81% 46%	83 63
Petersen (2019)	P, SC	1) PET/CT 2) MRI	68Ga PSMA 3T, DWI	20	5% IR 95% HR	Median 23 13/20, 65%	1) 2 2) 2, B	1) 39% 2) 36%	100% 83%	47% 42%	100% 80%	60 53
Van Leeuwen (2019)	R, SC	1) PET/CT 2) mpMRI (PIRADS, ESUR)	68Ga PSMA 1.5T, DWI, DCE	140	21% IR 79% HR	Median 16 51/140, 36%	Diff, B	1) 53% 2) 14%	88% 99%	76% 67%	71% 88%	NR
Yilmaz (2019)	R, SC	1) PET/CT 2) mpMRI (PIRADS v2)	68Ga PSMA 3T, DWI, DCE	Subgroup 10	NR	Median NR 2/10, 20%	1) 2 2) 1, B	1) 100% 2) 100%	100% 38%	100% 29%	100% 29%	100 50
Zhang (2017)	R, SC	1) PET/CT 2) mpMRI	68Ga PSMA 3T, DWI, DCE	42	40% IR 60% HR	Mean 7 15/42, 36%	1) 3, 2) 1, B	1) 93% 2) 93%	96% 96%	96% 96%	93% 88%	NR
Billing (2015)	R, SC	mpMRI (non-academic centers)	1.5 or 3T 59 DWI 57 SPCT	Subgroup 54	GS mean 7 PSA mean 12ng/ml	11/54, 20%	Diff., B	67%	92%	67%	92%	87
Vag (2014)	P, SC	1) PET/CT 2) MRI	11C-choline 1.5T, DWI	34, 76 regions	IR/HR	Per region 33/76	2, NR	1) 70% 2) 70%	91% 79%	NR	NR	83 79
Van den Bergh (2015)	P, SC	1) PET/CT 2) MRI	11C- choline 1.5T, DWI	75, risk on Partin tables ≥10+<35% and cN0 on cCT	GS 7+8 81% PSA median 10ng/ml	Median 21 37/75, 49%	1) 1 2) 1, B	1) 19% 2) 36%	90% 95%	53% 61%	64% 87%	55 66
Heck (2014)	P, SC	1) PET/CT 2) MRI	11C-choline 1.5 T, DWI	33	12% IR 88% HR	Median 30 14/33, 42%	1, B	1) 57% 2) 57%	90% 79%	74% 71%	80% 67%	76 70
Pinquay (2015)	R, SC	1) PET/CT 2) mpMRI	18F-FCH 1.5T, DWI, DCE, ERC	47	HR	Mean 11 9/47, 19%	1) 1 2) 1, B	1) 78% 2) 33%	94% 91%	94% 84%	78% 50%	NR
Selnaes (2018)	P, SC NCT02076503	1) PET/MRI 2) MRI	18F FACBC 3T, DWI, DCE, SPCT	26	HR	Median 20 10/26, 38%	2, B	1) 40% 2) 40%	100% 88%	73% 70%	100% 67%	77 69

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Abbreviations:

pp per patient

NPV negative predictive value

PPV positive predictive value

AUC Area under the ROC curve

R retrospective

P prospective

SC single center

MC multicenter

LN lymph nodes

mp/WB MRI multiparametric/whole body magnetic resonance imaging

PIRADS Prostate Imaging Reporting and Data System

ESUR European Society of Urogenital Radiology

DWI diffusion weighted imaging

DCE dynamic contrast enhanced

SPCT spectroscopy

ERC endorectal coil

PET/CT positron emission tomography/computed tomography

PSMA prostate specific membrane antigen

18F-FCH 18F-Fluorocholine

18F FACBC 18F-Fluciclovine

cCT contrast enhanced computed tomography

ISUP International Society of Urological Pathology

LR, IR, (V)HR low-, intermediate-, (very) high-risk patients

GS Gleason score

PSA prostate specific antigen

B blinded

NB not blinded

NR not reported

^**

enlarged on MRI/restricted diffusion LNs

3.4.1. PSMA

Twenty-four studies examined performance of 68Ga-PSMA-PET for N staging and reported an overall high specificity of 80 – 100%, while varying sensitivity of 33 – 100%.^{9, 21, 31, 32, 78, 82, 87, 91–107} However, most studies were limited by small patient sample and low event rates with large confidence intervals, ranging in some between 0 to 100%. Besides study design, size of lymph node metastases (LNM) was a limiting factor. Although PSMA-PET is thought to perform better than conventional imaging, based on morphological signs, size of LNM was noted in most studies as an important limitation with correctly identified LNM to be somewhere around ≥10mm.^{31, 32, 91, 96, 100, 101, 104–108} Yaxely et al. reported sensitivity of 38% and specificity 94% among 208 intermediate- to high-risk patients.¹⁰¹ Histopathological examination revealed LNM in 55 men (26%). PSMA-PET/CTs were evaluated by experienced nuclear physician radiologists. In this study, PSMA-PET/CT correctly identified only 15% of LNM that were <5mm of size. Furthermore, Maurer et al. showed sensitivity and specificity of PSMA-PET/CT to detect LNM of 66% and 99% while accuracy reached 89% in a cohort of 130 men, including 41 (32%) with LNM. Maximum size of missed LNM by PSMA-PET/CT was 3mm (1-5mm). Zhang et al. reported sensitivity of 93% and specificity of 96% among 42 men including 15 (36%) with LNM.¹⁰⁷ Notably, >80% of all LNM in this study were >10mm in size.

PSMA-PET/CT might not perform inferior to existing prediction tools such as the MSKCC or Briganti nomograms or the Partin Tables.^{21, 78, 93} Thalgott et al. found largest AUC for PSMA-PET/CT (0.8) but this was not statistically different to AUC obtained with the MSKCC nomogram (0.77) or Partin Tables (0.67).⁷⁸ A model integrating information of PSMA-PET/CT into MSKCC nomogram achieved AUC of 0.87. However, external validation is pending. Furthermore, including quantitative PET parameters such as SUV_max, PSMA_vol might improve accuracy.⁹³ Likewise, this has to be confirmed in further studies.

Six studies compared MRI to PSMA-PET/CT or PET/MRI.^{82, 87, 104–107} Results remained inconclusive as most studies contained only few patients (N=10 – 42) and reported mixed results. Leeuwen et al. observed better sensitivity for PSMA-PET/CT compared to 1.5T mpMRI (53% vs. 14%) in a cohort of 140 men including 51 (36%) with LNM.⁸² A smaller study by Zhang et al. described similar performance of high resolution, 3T mpMRI vs. PSMA-PET/CT in detection of LNM (sensitivity: 93% and specificity: 96%).¹⁰⁷ However, this study included a high proportion of LNM >10mm, which might have contributed to the favorable results.

3.4.2. 11C-Choline

As a phosphatidylcholine, 11C-Choline is part of cellular membranes and has less urinary excretion than other choline derivates resulting in favorable tumor-to-background ratio.¹⁰⁹ We identified a total of five studies on 11C-Choline for primary N staging. Sensitivity ranged between 10% and 70% and specificity between 76% and 100%.^{103, 110–113} As previously reported studies were highly heterogeneous with respect to sample size, patient characteristics or number of examined LN. Three studies compared 11C-Choline-PET/CT to diffusion-weighted (DW)-MRI and reported non-inferior performances although studies were limited by small sample size.^110–112 Interestingly, Vag et al. thought to define optimal ADC and SUVmean cutoff values for prediction of LNM. Highest sensitivity and accuracy for 11C-Choline PET/CT and DW-MRI were observed for SUVmean threshold of 2.5 and ADC of 1.01×10⁻³ mm²/s. However, the study included only 34 intermediate- and high-risk patients and findings need further confirmation.¹¹⁰ A small study including twelve patients directly compared 11C-choline- to PSMA-PET/MRI and reported similar sensitivity, but higher accuracy for PSMA-PET/MRI.¹⁰³

3.4.3. 11C-Acetate

Similar to 11C-Choline, 11C-Acetate offers the advantage of minimal urinary excretion with the benefit of low background radioactivity. Only three reports on the use of 11C-Acetate-PET/CT for N staging were identified.^114–116 All were prospective, including nine to 102 patients. The largest series by Haseebuddin et al., analyzed 102 patients with preoperative 11C-Acetate-PET/CT including 21 with LNM.¹¹⁵ Sensitivity and specificity were 68% and 78%. Interestingly, patients with false positive findings had worse treatment-failure free survival rates compared to patients with true negative results.

3.4.4. 18F-Fluorocholine

The PET tracer FCH has considerably longer half-life compared to 11C-Choline.¹¹⁷ However, urinary excretion remains substantially higher. We identified five studies on FCH-PET/CT in primary PCa staging (Table 2).^{60, 117–120} The time period for our literature search might have contributed to the limited number on studies on FCH-PET/CT. With limitations analogues to previous modalities, reported sensitivity of FCH-PET/CT ranged between 10% and 78% and specificity between 69% and 100%. Poulsen et al. reported sensitivity of 73% among 210 patients including 41 (20%) with LNM. Median number of LN removed was five and therefore relatively low. Mean diameter of true positive nodes was significantly larger compared to mean diameter of true negative nodes (10.3mm vs. 4.6mm).¹²⁰ Only one study compared FCH-PET/CT to DW-MRI and reported superior performance of FCH-PET/CT.⁶⁰ However, this study included only 47 patients with as few as nine having LNM.⁶⁰

3.4.5. 18F-Fluciclovine

Within three studies, including 26-28 patients, sensitivity and specificity of FACBC-PET/CT or -PET/MRI ranged between 14 – 76% and 86 – 100%.^{37, 121, 122} Consistent with reports on other PET tracers, LN size represents the main limitation with inability to detect LNM below 7-8mm.¹²² Only one out of seven patients was correctly identified in the study by Jambor et al., reporting on 26 patients that underwent FACBC-PET/CT and PET/MRI in a single center.³⁷ Median size of missed LNM was <8mm. Selnaes et al. compared FACBC-PET/MRI results to 3T mpMRI and reported similar sensitivity of 40% but higher specificity for FACBC-PET/MRI in 28 patients, including ten (38%) with LNM.¹²²

3.4.6. mpMRI

Nineteen studies reported on MRI for N staging in primary PCa. Similar to the results observed for local staging, there was large variation in patient sample and MRI techniques, resulting in wide range of sensitivity from 14% to 100%.^{10, 22, 39, 60, 82, 87, 102, 104, 106, 107, 110–112, 122–127} With the exception of some small case series, specificity remained high (Table 2). Most studies examined the role of DW-MRI, with the advantage of imaging without need for exogenous radiolabelled tracers or contrast agents. Similar to previous modalities, several studies highlighted the importance of LNM size.^{60, 104, 106, 111, 126} Usually, LN are assumed to be suspicious on MRI with short axis of >10mm in oval or >8mm in round shaped. In this review, size of truly detected LNM was somewhat >10mm.^{60, 126} Some articles suggested other parameters of mpMRI such as PIRADS lesion score or apparent diffusion coefficient values to be more accurate in predicting LNM than size.^{104, 110, 123, 125} For example, Brembilla et al. analyzed 101 patients with risk for LNM of >10% on Briganti nomogram and reported sensitivity for detection of LNM of 91% for presence of PIRADS ≥4 lesions or tumor volume ≥1cc compared to only 17% and 33% sensitivity for presence of enlarged LN or restricted diffusion LN.¹²³ In twelve studies, MRI was compared to PET/CT scans.^{60, 82, 87, 102, 104, 106, 107, 110–112, 122, 124} Results were reported within the different PET/CT sections and Table 2.

3.5. M stage: Detection of metastatic disease

Overall, 24 studies examined imaging for M stage and reported sensitivity of 80 – 100%. Ten studies were prospective and this section includes results of the first RCT on PSMA-PET/CT.¹²⁸

3.5.1. PSMA

Six studies were found to evaluate the role of PSMA-PET/CT and reported overall favorable sensitivity and specificity for detection of bone metastases.^128–133 In all studies, PSMA-PET/CT was compared and outperformed either conventional imaging (bone scintigraphy +/− CT/MRI), single photon emission computed tomography (SPECT) or other imaging modalities such as NaF-PET/CT or whole body MRI (WB-MRI). The largest and most recent report represents the only RCT in this setting. Within the proPSMA trial, Hofman et al. reported the results of a multicenter, two-arm randomized study comparing PSMA-PET/CT to conventional imaging (contrast enhanced CT and bone scan with SPECT-CT).¹²⁸ A total of 302 patients with high-risk characteristics underwent randomization. The authors observed a significantly higher accuracy for PSMA-PET compared to conventional staging (92% vs. 65%) for the entire cohort (N and M staging) as well as for distant metastases (95% vs. 74%). Sensitivity and specificity in detection of metastatic disease were 92% and 99% compared to 54% and 93%, respectively for conventional imaging. Interestingly, patients undergoing conventional imaging exhibited 10·9 mSv higher radiation exposure than PSMA-PET/CT patients. Moreover, less equivocal findings were described using PSMA-PET/CT compared to conventional imaging resulting in reduction of further investigations, which are often needed in case of inconclusive findings. Furthermore, two prospective and three retrospective studies with sensitivities ranging between 96 – 100% and accuracy of 95 – 100% were found. Lengana et al. reported prospectively on a cohort of 113 patients undergoing PSMA-PET/CT and bone scintigraphy.¹³¹ With an overall detection rate of 25/26 patients with bone metastases, sensitivity and specificity for PSMA-PET/CT were favorable with 96% and 100%. One study thought to compare WB-MRI, PSMA- and NaF-PET/CT and reported significantly higher accuracy for PSMA-PET/CT than WB-MRI, while there was no statistical difference between PSMA- and NaF-PET/CT.¹³³ However, this study was limited by the small and inhomogeneous study population, including only ten patients for staging purposes, three under Active Surveillance/Watchful Waiting and 37 under ADT.¹³³

3.5.2. 18F-Sodiumfluoride

Another promising bone-specific radiopharmaceutical in the assessment of bone metastases is NaF. NaF binds to mainly osteoblastic bone lesions and - in combination with CT – may offer whole body examination.¹³⁴ Six studies, including 37 – 211 patients, assessed the use of NaF-PET/CT and reported overall favorable sensitivity from 88 – 100%.^{133, 135–139} Consistent in all studies, NaF-PET/CT performed better than conventional imaging and had less equivocal findings requiring additional imaging for further clarification.^{135, 137, 139} Zacho et al. reported high interobserver agreement in the detection of bone metastases of two well trained radiologists (Cohen’s kappa 0.89).¹³⁸ Poulsen et al. compared NaF- and FCH-PET/CT to bone scintigraphy for detection of spine metastases and reported similar performance of NaF- and FCH-PET/CT while superior performance of NAF-PET/CT compared to bone scintigraphy.¹³⁹ However, the study included only pre-selected patients with bone metastases and might not be applicable to other patients.

3.5.3. 18F-Fluorocholine

Six studies, including 18 – 143 patients, examined the performance of FCH-PET/CT. Reported sensitivity and specificity ranged from 80 – 100% and 91 – 100%, respectively.^{118, 119, 139–142} Comparison of FCH-PET/CT to other imaging modalities including conventional imaging, WB-MRI or NaF-PET/CT was performed in five studies.^{119, 139–142} While FCH-PT/CT was declared to perform better than conventional imaging, most studies included only few patients and had low event rates.^{119, 140, 141} Metser et al. compared FCH-PET/CT or PET/MRI to WB-MRI (n=48) and did not find a statistically significant difference with respect to skeletal metastases while the authors observed an advantage for FCH-PET/CT in the detection of non-regional LNM.¹⁴⁰

3.5.4. other PET tracers

Three studies reported on other imaging modalities such as 18FDG-, 11Acetate- or 13N-Ammonia- PET/CT and reported promising results.^{124, 143, 144} Two studies assessed use of FDG-PET/CT for primary staging. While FDG-PET/CT remained less useful for relatively well-differentiated tumors, favorable sensitivity for FDG-PET/CT (90 – 100%) was observed in high-risk patients.^{124, 144, 145} When compared to 13N-Ammonia, both tracers had perfect sensitivity for detection of bone metastases.¹⁴⁴ One study reported favorable sensitivity and specificity for 11-Acetate-PET/CT versus bone scintigraphy in detection of bone metastases (100% vs. 69% and 98% vs. 94%).¹⁴³ However, all studies were limited by small patient number, low event rate and preselected patients that hinder final conclusions.

3.5.5. WB-MRI

Six studies reported on WB-MRI and additional three on pelvic MRI for M staging in newly diagnosed PCa.^{133, 136, 140, 142, 146–150} Sensitivity and specificity to predict bone metastases ranged between 74 – 100% and 83 – 100% for WB-MRI as well as 71 – 95% and 95 – 100% for pelvic MRI. However, study populations and event rates were highly heterogeneous resulting in extremely wide confidence intervals in some studies. Pasoglou et al. prospectively combined mpMRI and WB-MRI as a “one-step TNM staging” for detection of bone metastases in 30 high-risk patients.¹⁴⁶ Both non-irradiation imaging modalities were done within less than one hour during a single visit. Sensitivity and specificity were perfect (100%), though only nine patients had bone metastases. Eyrich et al. analyzed more than 600 primary PCa patients across all risk stages among 44 different academic and community practices that underwent mpMRI (pelvis to aortic bifurcation) in addition to bone scintigraphy.¹⁴⁸ Depending on mpMRI interpretation (including equivocal signs), performance was inferior or equal compared to bone scintigraphy. Four studies compared WB-MRI to other modern imaging modalities (PSMA-, NaF- and FCH-PET/CT).^{133, 136, 140, 142} Mosavi et al. reported favorable results for WB-MRI and NaF-PET/CT in high-risk patients (100% sensitivity for both).¹³⁶ However, only five patients out of 49 patients had bone metastases. Likewise, Metser et al. reported similar performance of FCH-PET/CT and WB-MRI in detection of bone metastases (see 3.5.1.3).¹⁴⁰

4. Discussion

This systematic review provides an overview on modern imaging modalities for TNM staging of newly diagnosed PCa. We identified a variety of studies and imaging modalities, especially with respect to N and M staging. Most studies on T stage reported on mpMRI, which has gained more and more attention within the last decade. In the latest update of the EAU guidelines, there is a strong recommendation for the use of mpMRI in the pre-biopsy setting.¹ However, no such recommendation for further T or N staging exists. The “gold” standard for N staging represents standard or extended PLND, which causes morbidity and may miss LNM outside the field. Identification of LNM for further treatment planning, especially for non-surgical patients, remains challenging. Compared to pelvic MRI, PET/CT offers the benefit of combined whole-body examination, resulting in detection of LNM outside the pelvic area.

In this review, sensitivity and specificity of modern imaging for T and N staging ranged from 0% to 100%; in short, its properties are unknown. The wide range of reported performance reflects the heterogeneity of included studies. Most studies were limited by insufficient sample size and low event rate with accordingly high level of uncertainty. In addition, 95% confidence intervals were often missing and in some studies, confidence intervals would range considerably wide around reported rates. Furthermore, differences in study populations, histopathological interpretations, evaluation methods and reader experience might contribute to this wide range. Moreover, image quality and imaging techniques are very important, especially for mpMRI. If quality of T2-WI is suboptimal, exact staging remains difficult and only few studies reported on this topic in detail. Therefore, comparisons of reported results and assessments of clinical significance have to be made with caution.

Level of radiological experience might be of importance and absence of central radiologic review as well as and inhomogeneous definition of outcome variables might also contribute to the unsatisfying results. Although, the ESUR tried to standardize reporting by introducing PIRADS and EPE score, presence of EPE or LNM still reflects subjective interpretation.

Possibly, imaging might improve local staging when combined with other clinical data and the incorporation into existing risk stratifications such as the MSKCC nomogram or Partin Tables. However, there are no external validations of those models so far. As there are only a handful of studies comparing different imaging modalities, at this moment, we cannot comment on superiority of one modality to another.

Most studies on T staging reported on MRI, while the clinical utility of other imaging modalities such as FACBC- or PSMA-PET/CT remains unknown. Table 4 provides an overview of study results.

Table 4.

Key findings of the systematic review and recommendations for future research purpose

Indication	Key findings	Recommended research
Overall	- heterogeneous study designs, definitions of outcome variables and imaging techniques - most studies were limited by insufficient sample size and low event rate with accordingly high level of uncertainty	- RCTs with adequate study sample and event rates - direct comparison between mpMRI and PET/CT with: - standardized reporting (PIRADS, ESUR), clear definitions and same techniques - blinding to clinical and pathological data - central pathological and radiological review - determination of different anatomical LN regions for LNI - external validation of models incorporating imaging results into existing tools - RCTs comparing different imaging modalities
EPE + SVI	- most studies reported on MRI - standardized reporting play an important role - reader experience and academic setting might improve performance - possible beneficial effect by adding imaging data to existing risk tools but no external validations so far
LNI	- PET seems more promising than MRI - size of lymph node metastases most important for detection among all modalities
M	- one RCT demonstrating superiority of PSMA-PET/CT to conventional staging, but: - no blinding - no comparisons between different imaging modalities - WB-MRI, NaF-PET/CT, FCH-PET/CT of unknown clinical utility	- first: RCTs evaluating role of WB-MRI, NaF- and FCH-PET/CT compared to conventional imaging - second: RCTs comparing different imaging modalities - blinding of radiologists and physicians to clinical data - central pathological and radiological review

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Abbreviations:

EPE extraprostatic extension

SVI seminal vesicle invasion

LNI lymph node invasion

M distant metastases

RCT randomized controlled trial

PET/CT positron emission tomography/computed tomography

PSMA prostate specific membrane antigen

NaF 18F-Sodiumfluoride

FCH 18F-Fluorocholine

mp/WB-MRI multiparametric/whole body magnetic resonance imaging

For N staging, the main limitation of conventional and functional imaging relies in identification of small sized LNM. Yet, the most promising tracer for N staging remains PSMA. Although other PET tracers such as 11C-Choline, 11C-Acetate or FCH offer some benefits compared to conventional staging, they seem to play only a minor role in light of PSMA-PET/CT.

In the era of new systemic treatment agents, correct identification of distant metastases remains crucial and one reason for high failure rates after local treatment might be caused by missed metastases on initial staging. Over the last years, the field of imaging for metastatic disease has rapidly evolved. Due to heterogeneous study populations, often mixing patients for primary and re-staging purposes as well as for metastatic castration resistant PCa, only a handful of reports met final inclusion criteria for this review.

Overall, modern imaging modalities such as PSMA-, NaF- or FCH-PET/CT as well as WB-MRI have shown superior results compared to conventional imaging; however, direct comparisons of different imaging modalities are missing. Analogous to T and N staging, small sample size and low event rates with wide confidence intervals limit validity of reported results.

The most promising and best-studied tracer represents 68Ga-PSMA. Results from the first RCT demonstrated its superiority to conventional imaging methods. Due to high specificity of the tracer and high tumor-to-background contrast, PSMA makes early identification of bone lesions even before osteolytic or osteoblastic changes possible.¹²⁸ PSMA-PET/CT resulted in fewer equivocal results than bone scintigraphy reducing the need for additional testing.¹³² By using a single modality such as PSMA-PET/CT, time, radiation dose and costs were spared. A responsible use of resources remains essential, not every patient needs whole body work-up. Imaging should be saved for patients at high-risk for metastatic disease while prevalence in low- or early intermediate-risk remains naturally low.¹³¹

Compared to PET/CT, WB-MRI offers the opportunity of an all-in-one TNM staging without irradiation. However, results for MRI work-up were inconsistent. In addition to previously mentioned limitations by study design, some studies reported excellent performance in detection of bone metastases while in fact other studies observed bone lesions, yet these rarely represented metastases.

There are several limitations of this systematic review. First, due to highly heterogeneous study cohorts, different definition of endpoints, varying imaging techniques, different reader/center experience, and absence of standardized protocols, we had to report our findings in a descriptive manner without pooling of data. Second, the review is limited by the quality of included studies, most being retrospective, lacking direct comparisons to other imaging modalities, including only few patients, had low event rates and wide confidence intervals with accordingly high level of uncertainty. Histological confirmation of distant metastases was not required; rather, we decided to include studies using at least a best value comparator consisting of imaging, biochemical, and clinical data at baseline and/or follow-up.

Finally, some studies might have been missed.

5. Conclusions

A variety of studies on modern imaging techniques for TNM staging in newly diagnosed PCa exist. For T and N staging, reported sensitivity of imaging such as mpMRI or PET/CT varied widely preventing clear recommendations. For M staging, the most promising technique is PSMA-PET/CT.

6. Future perspectives

Given the results of our review, most studies were limited by heterogeneity, small sample size and low event rate resulting in high level of uncertainty. Therefore, we need uniformity in data presentation on this topic. Our recommended standards for future reporting on accurate TNM staging are ideally large, prospective studies of 1.) mpMRI and 2.) PET/CT tracers using standardized imaging techniques, procedures and appropriate imaging-related reporting systems (Table 4). Studies need a clear definition of outcome variables, confirmed by pathological examination and clinical follow-up. For N-staging, predefined templates of anatomical LN regions are necessary to correlate imaging and pathological results. A central pathological and radiological review with blinding to all data is mandatory. Once, acceptable sensitivity and specificity is achieved, the next step is an RCT comparing different modalities such as mpMRI and PET/CT. For M staging, we need an RCT comparing PSMA-PET/CT to other modern imaging modalities (e.g. WB-MRI, NaF- and FCH-PET/CT). Furthermore, studies that externally validate the incorporation of imaging results into existing risk tools are necessary.

Supplementary Material

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Supplementary Figure 1. Risk of bias and study applicability according to QUADAS-2 criteria

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Supp table 1

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Table 3.

Studies reporting on imaging modalities for metastases staging in newly diagnosed prostate cancer

Author (year)	Study design	Imaging type	Tracer/sequences	No. Patients	Patient cohort	Endpoint/event rate	Standard reference	Reader, Blinding	Sensitivity	Specificity	NPV	PPV	Accuracy/AUC (%)
Hirmas (2019)	R, SC	1) PET/CT 2) BS	68Ga PSMA	21	HR GS ≥8 67% PSA median 38 ng/ml	Bone mets (per lesion) NR	Clinical, imaging (20CT, 16BS, 15MRI) baseline data + FU	2, NR	1) 100% 2) 63%	92% 88%	100% 70%	90% 83%	95 75
Hofman (2020) proPSMA	RCT, MC ACTRN12617000005358	1) PET/CT 2) cCT/BS with SPECT/CT	68Ga PSMA	302	HR ISUP ≥3 98% PSA ≥20ng/ml 22%	LN + Dist. mets. Overall: 87/295 mets: 48/295	Histology, clinical, biochemical and imaging FU at 6mo	Diff, NB	Overall: 1) 85% 2) 38% Metastases: 1) 92% 2) 54%	98% 91% 99% 93%	94% 76% 98% 91%	94% 67% 96% 59%	92 65 95 74
Janssen (2018)	R, SC	1) PET/CT 2) SPECT/CT	68Ga PSMA	54	NR	Bone mets 29/54	Clinical and imaging baseline data + FU	2, NR	1) 100% 2) 83%	100% 84%	NR	NR	100 83
Lengana (2018)	P, SC	1) PET/CT 2) BS	68Ga PSMA	113	Newly diagnosed, GS >7 54% PSA >20 75.2%	Bone mets 26/113	Histology, imaging (CT, MRI, skeletal) correlation + clinical FU	2, B	1) 96% 2) 73%	100% 87%	99% 92%	100% 63%	99 84
Pyka (2016)	R, SC	1) PET/CT 2) BS	68Ga PSMA	Subgroup 37	Mean PSA 45ng/ml	Bone mets NR	Clinical and imaging baseline + FU	2, NR	1) 100% 2) 57%	91-100%^* 65-96	NR	NR	100 77
Dyrberg (2019)	P, SC	1) PET/CT 2) PET/CT 3) WB-MRI	1) 68Ga PSMA 2) 18F-NaF 3T, DWI	55	10 staging 3 under AS/WW 37 ADT	Bone mets 20/55	Concordance between 3 index tests, clinical, biochemical and imaging FU of at least 0.5-1.5 years in case of disconcordance	2 each, B	1) 100% 2) 95% 3) 80%	100% 97% 83%	100% 97% 88%	100% 95% 73%	100 96 82
Fonager (2017)	P, MC	1) PET/CT 2) SPECT/CT 3) BS	18F-NaF	37	HR PSA ≥50ng/ml	Bone mets 27/37	Clinical, biochemical and imaging baseline +FU	2, B	1) 89% 2) 89% 3) 78%	90% 100% 90%	75% 77% 60%	96% 100% 96%	89 92 81
Mosavi (2012)	P, SC	1) PET/CT 2) WB-MRI	18F-NaF 1.5T, DWI	49	HR	Bone mets 5/49	Consensus imaging and clinical FU	2 each, B	1) 100% 2) 100%	91% 98%	56% 83%	100% 100%	NR
Wondergem (2018)	R, SC	1) PET/CT 2) BS	18F-NaF	104 NaF 122 BS	PSA median 1) 89ng/ml 2) 29ng/ml	Bone mets NR	Baseline imaging + clinical, biochemical, imaging FU at ≥6mo	2, B	1) 97-100%^* 2) 84-95%^*	98-100%^* 72-100%^*	95-100%^* 93-96%^*	98-100%^* 61-100%^*	98-99 79-95
Zacho (2020)	R, SC	PET/CT	18F-NaF	211	129 staging 67 BCR 23 mCRPC	Bone mets 64/211	Clinical, biochemical and imaging baseline +FU	2, B	88-91%^*	90-97%^*	94-97%^*	70-93%^*	NR
Poulsen (2014)	P, SC, NCT00956163	PET/CT 3) BS	1) 18F-NaF 2) 18F-FCH	50	Bone mets in primary BS, PSA median 84ng/ml	Spine mets NR	Spine MRI	4, B	1) 93% 2) 85% 3) 51%	54% 91% 82%	78% 75% 43%	82% 95% 86%	81 87 61
Metser (2018)	P, SC	1) PET/MRI 2) PET/CT 3) WB-MRI 4) CT/BS	18F-FCH 3T, DWI	58, 10 PET/MRI, 48 PET/CT + WB-MRI	HR	Metastases 77 met sites	Histology, imaging and clinical FU Analyses per site	PET: 1 MRI: 2, NR	1) 100% 2) 94% 3) 74% 4) 64%	NR	NR	NR	NR
Mortensen (2019)	P, SC, NCT02232685	1) PET/CT 2) BS	18F-FCH	143	GS median 7 PSA median 18ng/ml	Bone mets 8/143	Consensus of BS+PET+MRI	2, NR	1) 100% 2) 38%	96% 85%	NR	NR	NR
Evangelista (2015)	R, SC	1) PET/CT 2) BS	18F-FCH	48	40% IR 60% HR	Bone mets 11/48	Clinical, biochemical and imaging FU	2, NR	1) 100% 2) 90%	92% 77%	100% 94%	79% 64%	94 81
Gauvin (2019)	R, SC	PET/CT	18F-FCH	76	HR	Metastases NR	Histology, clinical and imaging FU at least 6Mo	1, NR	86%	100%	98%	100%	NR
Johnston (2019)	P, SC	1) PET/CT 2) WB-MRI 3) BS	18F-FCH 3T, DWI	Subgroup 18	11% IR 89% HR	Bone mets 5/18	Clinical and imaging baseline +FU	2, B	1) 80% 2) 90% 3) 60%	92% 88% 100%	92 97% 87%	80% 81% 100%	NR
Strandberg (2016)	R, SC	1) PET/CT 2) BS	11C-acetate	66	HR	Bone mets	Concordance of index tests, clinical, biochemical and imaging FU in case of disconcordance	2, NR	1) 100% 2) 69%	98% 94%	100% 93%	93% 75%	NR
Shen (2018)	R, SC	1) PET/CT 2) BS	18F-FDG	46	HR	Bone mets	Clinical and imaging FU at least 12mo	2, B	1) 90% 2) 90%	92% 80%	92% 91%	91% 79%	NR
Yi (2016)	R, SC	PET/CT	1) 13N-ammonia 2) 18F-FDG	26	GS ≥8 or PSA >20ng/ml or ≥T2c	Bone mets	Histology, clinical and imaging baseline + FU 4mo	2, B	1) 100% 2) 100%	100% 83%	NR	NR	NR
Pasoglou (2014)	P, SC	1) WB-MRI 2) BS + TXR	3T, DWI, DCE	30	HR	Bone mets 9/30	Clinical, biochemical and imaging baseline +FU at 6mo	2, NR	1) 100% 2) 89%	100% 90%	100% 95%	100% 80%	100 90
Pasoglou (2015)	P, SC	WB-MRI	3T, DWI 1) 2D 2) 3D	30	HR	Bone mets NR	Clinical, biochemical and imaging baseline +FU at 6mo	1, B	1) 90% 2) 100%	100% 100%	95% 100%	100% 100%	95 100
Eyrich (2020)	R, MC	1) mpMRI (pelvis to aortic bifurcation) 2) BS	1.5-3T, NR	646	Mostly HR PSA median 9ng/ml	Bone mets 38/646	Imaging and clinical FU	Diff, B	1) 42-71%^* 2) 68%	95-98%^* 98%	96-98%^* 98%	47-67%^* 63%	NR
Vargas (2017)	R, SC	MRI (prostate)	1.5-3T, +/−ERC	228	33% LR 35% IR 32% HR	Bone mets 53/228	Histology, clinical and imaging baseline + FU at least 12mo	2, B	89/67%^#	98/99%^#	NR	NR	97/90^#
Woo (2016)	R, SC	mpMRI (prostate)	3T, DWI, DCE	308	119 HR	Bone mets 21/308	Histology, clinical and imaging baseline + FU	2, NR	95%^*	99-100%^*	100%^*	87-100%^*	NR

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Abbreviations:

NPV negative predictive value

PPV positive predictive value

AUC Area under the ROC curve

R retrospective

P prospective

RCT randomized controlled trial

SC single center

MC multicenter

PET/CT positron emission tomography/computed tomography

SPECT single photon emission computed tomography

PSMA prostate specific membrane antigen

18F-NaF 18F-Sodiumfluoride

18F-FCH 18F-Fluorocholine

18F-FDG 18F-Fluorodeoxyglucose

18F FACBC 18F-Fluciclovine

cCT contrast enhanced computed tomography

BS bone scintigraphy

TXR target X-ray

mp/WB-MRI multiparametric/whole body magnetic resonance imaging

DWI diffusion weighted imaging

DCE dynamic contrast enhanced

ERC endorectal coil

LR, IR, HR low-, intermediate-, high-risk patients

GS Gleason score

PSA prostate specific antigen

BCR biochemical recurrence

mCRPC metastatic castration resistant prostate cancer

LN lymph nodes

FU follow-up

B blinded

NB not blinded

NR not reported

optimistic/pessimistic approach (equivocal results)

among different readers

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supp fig 1

Supplementary Figure 1. Risk of bias and study applicability according to QUADAS-2 criteria

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PERMALINK

The role of MRI and PET/CT in the primary staging of newly diagnosed prostate cancer: a systematic review of the literature

Raisa S Abrams-Pompe

Stefano Fanti

Ivo G Schoots

Caroline M Moore

Baris Turkbey

Andrew J Vickers

Jochen Walz

Thomas Steuber

James A Eastham

Abstract

Context:

Objective:

Evidence acquisition:

Evidence synthesis:

Conclusions:

Patient summary:

1. Introduction

2. Evidence Acquisition

2.1. Search strategy

2.2. Study selection

2.3. Data extraction

3. Evidence Synthesis

3.1. Characteristics of included articles

Figure 1.

3.2. Quality of studies

3.3. T stage: Detection of extraprostatic extension and seminal vesicle invasion

Table 1a.

Table 1b.

3.3.1. mpMRI

3.3.1.1. Risk-stratification

3.3.1.2. Reader experience

3.3.1.3. Standardized reporting

3.3.1.4. Setting

3.3.1.5. Other

3.3.2. PSMA-PET

3.3.3. Comparisons and clinical risk tools

3.4. N stage: Detection of lymph node metastases

Table 2a.

Table 2b.

3.4.1. PSMA

3.4.2. 11C-Choline

3.4.3. 11C-Acetate

3.4.4. 18F-Fluorocholine

3.4.5. 18F-Fluciclovine

3.4.6. mpMRI

3.5. M stage: Detection of metastatic disease

3.5.1. PSMA

3.5.2. 18F-Sodiumfluoride

3.5.3. 18F-Fluorocholine

3.5.4. other PET tracers

3.5.5. WB-MRI

4. Discussion

Table 4.

5. Conclusions

6. Future perspectives

Supplementary Material

Table 3.

References

Associated Data

Supplementary Materials

ACTIONS

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