Biomarkers Prostate

Imaging guidelines in newly diagnosed prostate cancer

Guideline	Categories	Imaging recommendation
EAU	Low-risk*	- No imaging
	Intermediate-risk*; predominantly GI 4	- Multiparametric MRI for local staging ^1! - CT-abdomen/pelvis - Bone scan ^{2, 3, 4, 5!}
	High-risk*	- Multiparametric MRI for local staging - CT-abdomen/pelvis - Bone scan^{2, 3, 4, 5!}
	General / any risk	- No CT / TRUS for local staging - No Choline-PET for detection of LN-metastases - No final recommendation on Ga/F-PSMA PET - No final recommendation on WB-MRI
NCCN (Version : 2.2017)	If life expectancy >5y or asymptomatic AND: - T1 and PSA >20ng/ml - T2 and PSA >10ng/ml - Gleason 9 - T3 or T4	- Bone scan^{2, 3, 4, 5!}
	Symptomatic AND: - T3; T4; - T1-T2 and nomogram >10% risk of LN-metastases Cagiannos I., et al ^7!	- CT/MRI
AUA/ASTRO SUO 2017	Very low and Low risk*	- No CT-abdomen/pelvis or Bone scan
	Unfavourable Intermediate/ High-Risk*	- CT/MRI - Bone scan
IKNL (Guideline prostate cancer, version 2.1)	- PSA >20ng/ml - cT3 - Gleason 8 - Symptomatic	- Bone scan or choline PET^6!
	General / any risk	- Multiparametric MRI for primary diagnosis (if available) ^1! - Multiparametric MRI for staging (only if relevant for therapy) - No CT for staging - No routine Choline-PET for primary Staging

* Low-risk: PSA < 10 ng/mL; GS < 7 (ISUP grade 1); cT1-2a
Intermediate-risk: PSA 10-20 ng/mL; GS 7 (ISUP grade 2/3) or cT2b
High-risk: PSA > 20 ng/mL; or GS > 7 (ISUP grade 4/5); or locally advanced

x Very Low Risk: PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a AND <34% of biopsy cores positive AND no core with >50% involved, AND PSA density <0.15 ng/ml/cc
Low Risk: PSA <10 ng/ml AND Grade Group 1 AND clinical stage T1-T2a
Intermediate Risk: PSA 10-<20 ng/ml OR Grade Group 2-3 OR clinical stage T2b-c
Favorable: Grade Group 1 (with PSA 10-<20) OR Grade Group 2 (with PSA<10)
Unfavorable: Grade Group 2 (with either PSA 10-<20 or clinical stage T2b-c) OR Grade Group 3 (with PSA < 20) High Risk: PSA >20 ng/ml OR Grade Group 4-5 OR clinical stage >T3 OR locally advanced

Footnotes

Ahmed HU, El-Shater Bosaily A, Brown LC, Gabe R, Kaplan R, Parmar MK, Collaco-Moraes Y, Ward K, Hindley RG, Freeman A, Kirkham AP, Oldroyd R, Parker C, Emberton M; PROMIS study group. Diagnostic accuracy of multi-parametric MRI and TRUS biopsy in prostate cancer (PROMIS): a paired validating confirmatory study. Lancet. 2017 Feb 25;389(10071):815-822.
Briganti A, Passoni N, Ferrari M, et al. When to Perform Bone Scan in Patients with Newly Diagnosed Prostate Cancer: External Validation of the Currently Available Guidelines and Proposal of a Novel Risk Stratification Tool. Eur Urol 2010; 57: 551–8.
Shen G, Deng H, Hu S, Jia Z. Comparison of choline-PET/CT, MRI, SPECT, and bone scintigraphy in the diagnosis of bone metastases in patients with prostate cancer: a meta-analysis. Skeletal Radiol. 2014; 43: 1503–13.
Zacho HD, Manresa JAB, Aleksyniene R, et al. Three-minute SPECT/CT is sufficient for the assessment of bone metastasis as add-on to planar bone scintigraphy: prospective head-to-head comparison to 11-min SPECT/CT. EJNMMI Res 2017; 7: 1.
Palmedo H, Marx C, Ebert A, et al. Whole-body SPECT/CT for bone scintigraphy: Diagnostic value and effect on patient management in oncological patients. Eur J Nucl Med Mol Imaging 2014; 41: 59–67.
Beheshti M, Imamovic L, Broinger G, et al. 18F choline PET/CT in the preoperative staging of prostate cancer in patients with intermediate or high risk of extracapsular disease: a prospective study of 130 patients. Radiology 2010; 254: 925–33.62.
Cagiannos I, Karaciwicz P, Eastham JA, et al. A Preoperative Nomogram Identifying Decreased Risk of Positive Pelvic Lymph Nodes in Patients With Prostate Cancer. J Urol 2003; 170: 1798–803.

Imaging guidelines at biochemical recurrence of prostate cancer

Guideline	Categories	Imaging recommendation
EAU	After prostatectomy:
	- PSA <1ng/ml	- No imaging
	- PSA >1ng/ml	- Choline or PSMA-ligand PET^8!
	After radiotherapy: (If fit enough for curative salvage)	- Multiparametric MRI - Choline-PET^{9, 10, 11!} - Ga-PSMA PET no standard tool, yet should be considered if available^{12, 13, 14, 15, 16, 17, 18!}
	General / any risk: - Only if PSA >10ng/ml - PSAdt <6mnth - PSA velocity>0,5ng/ml/mo	- CT-abdomen/pelvis^{19, 20!} - Bone scan^{19, 20!} - No final recommendation on WB-MRI^{21, 22!}
NCCN (Version : 2.2017)	After prostatectomy:	- Bone scan
	After Radiotherapy If candidate for local therapy (T1-2, Nx or N0; Life expectancy >10y; PSA>10ng/ml)	- X-ray chest - Bone scan - Prostate MRI Consider: - CT/MRI-abdomen/pelvis - C-11 Choline PET^23!
IKNL (Guideline prostate cancer, version 2.1)	- PSA >5ng/ml - PSA >1ng/ml and PSAdt <3mo - Gleason 8	- Choline PET - Bone scan only if PSA >20ng/ml
	General / any risk	- No CT for staging Consider: - Multiparametric MRI for local recurrence

Footnotes

Imaging guidelines at the castrate resistant stage of prostate cancer

Guideline	CRPC (APC)	Imaging recommendation	comments
EAU	- PSA >2ng/ml - Symptomatic	- Bone scan ^{24, 25, 26, 27, 28, 29!} - CT	(If negative repeat when PSA >5ng/ml and after PSAdt)
	- mCRPC - monitoring of treatment	- CT-chest - CT-abdomen/pelvis - Bone scan	(Repeated every 6 months)
NCCN(Version: 2.2017)	Castration-naïve	- Bone scan - X ray-chest - CT/MRI-abdomen/pelvis with and without contrast Consider:- Choline PET^{30, 31!}
	Monitoring mCRPC	- CT/MRI - Bone scan	(Every 6-12 months) (Every 8-12 weeks)
APCCC 2017 (Delphi method >75% agreement)	Oligometastatic castration-naïve Pca	-NoCT-abdomen/pelvis or Bone scan
	Staging and monitoring mCRPC when treating with Ra-223	- CT-Thorax/Abdomen - Bone scan
APCC 2015	mCRPC	- CT-chest - CT-abdomen/pelvis - Bone scan - No routine WB-MRI or PET/CT for staging	(Before start of treatment)
PCWG3	If locally persistent/recurrent	- Multiparametric MRI
	All patients	- CT-chest(<5 mm slices) - CT-abdomen/pelvis (<5 mm slices) - Bone scan - WB-MRI and PET/CT (all tracers) not recommended

Footnotes

Miyoshi Y, Yoneyama S, Kawahara T, et al. Prognostic value of the bone scan index using a computer-aided diagnosis system for bone scans in hormone-naive prostate cancer patients with bone metastases. BMC Cancer 2016; : 1–7.
Poulsen MH, Rasmussen J, Edenbrandt L, et al. Bone Scan Index predicts outcome in patients with metastatic hormone-sensitive prostate cancer. BJU Int 2016; 117: 748–53.
Reza M, Bjartell A, Ohlsson M, et al. Bone Scan Index as a prognostic imaging biomarker during androgen deprivation therapy. EJNMMI Res 2014; 4: 58.
Armstrong AJ, Kaboteh R, Carducci MA, et al. Assessment of the bone scan index in a randomized placebo-controlled trial of tasquinimod in men with metastatic castration-resistant prostate cancer (mCRPC). Urol Oncol 2014; 32: 1308–16.
Kaboteh R, Gjertsson P, Leek H, et al. Progression of bone metastases in patients with prostate cancer - automated detection of new lesions and calculation of bone scan index. EJNMMI Res 2013; 3: 64.
Ulmert D, Kaboteh R, Fox JJ, et al. A novel automated platform for quantifying the extent of skeletal tumour involvement in prostate cancer patients using the bone scan index. Eur Urol 2012; 62: 78–84.
Ceci F, Castellucci P, Nanni C, Fanti S. PET/CT imaging for evaluating response to therapy in castration-resistant prostate cancer. Eur J Nucl Med Mol Imaging 2016; 43: 2103–4.
Schwarzenböck SM, Eiber M, Kundt G, et al. Prospective evaluation of [11C]Choline PET/CT in therapy response assessment of standardized docetaxel first-line chemotherapy in patients with advanced castration refractory prostate cancer. Eur J Nucl Med Mol Imaging 2016; 43: 2105–13.

Imaging characteristics and evidence level

Imaging modality		Newly diagnosis staging		BCR		CRPC
		ROC characteristics	Evidence level	ROC characteristics	Evidence level	ROC characteristics	Evidence level
SIM	CT	Node: Sens + Spec ++	2a/B	Limited value and not recommended unless a high PSA value	3b/B	NA	2a/B
	Bone scintigraphy	Bone: Sens +++ Spec +++	3a/B	Limited value and not recommended unless PSA >10 ng/mL	3b/B	‘2+2 rule’ recommended by PCWG	3b/B
MIM	18F-NaF	Bone: Sens ++++ Spec +++ PPV+++ NPV ++++	2a/B	NA	NA	NA	NA
	^18!F-Choline	Bone: Sens +++ Spec ++++ Node: Sens ++ Spec ++++ PPV+++ NPV ++++	2a/B 1b/A	Patient basis Sens +++ Spec +++ Influenced by PSA level at recurrence	2a/B	Bone & soft tissue: Sens++++ Spec ++++ PPV++++ NPV ++++	2b/B
	WB-MRI with DWI	Bone: Sens++++ Spec++++ AUC ++++	2a/B	Positive at low PSA levels	2b/B	Anatomic and functional criteria	2b/B
	PSMA	Bone: Sens +++ Spec ++++ Node: Sens++ Spec++++ PPV+++ NPV +++	2b/B	Patient basis: Sens +++ Spec +++ Influenced by PSA level at recurrence	2a/B	Not reliable for AR axis targeting treatments	NA

“+” <50%;
“++” 50%-69%;
“+++” 70%-89%;
“++++” 90%

AR= androgen receptor;
BCR= biochemical relapse;
CRPC= castration-resistant prostate cancer;
DWI=diffusion weighted imaging;
NA=no adequate data in this population or similar ROC and evidence level to staging;
NPV=negative predictive value;
PPV=positive predictive value;
PCWG=prostate cancer working group;
PSA= prostate-specific antigen;
PSMA= prostate-specific membrane antigen;
ROC= receiver operating characteristic;
Sens= sensitivity;
Spec=specificity;
WB-MRI=whole body- magnetic resonance imaging