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Shifting paradigms in prostatic cancer imaging
M P MR I & 6 8 G A - P S MA - P ET
G E O R G E E . B O U K H E I R
P G Y 4 U R O L O G Y R E S I D E N T
N O V E M B E R 2 0 1 6
Evolution in prostate cancer diagnosis
I. In 1980 sextant scheme was introduced to detect (all)prostate cancers.
II. In 1990 12 core PBx and Saturation PBx wereintroduced to detect and, at the same time,characterize (all) prostate cancers.
III. In 2016 we feel the need to detect and characterizeonly the significant prostate cancers.
Current limitations of prostate biopsy
J Urol. 2014 Sep; 192(3): 648–658.
Published online 2014 Apr 21. doi
What is multiparametric MRI?
Reporting of mpMRI: PIRADS v.2•PI-RADS 1 – Very low (clinically significant cancer is highly unlikely to be present)
•PI-RADS 2 – Low (clinically significant cancer is unlikely to be present)
•PI-RADS 3 – Intermediate (the presence of clinically significant cancer is equivocal)
•PI-RADS 4 – High (clinically significant cancer is likely to be present)
•PI-RADS 5 – Very high (clinically significant cancer is highly likely to be present)
PIRADS v.2T2 - Transition Zone
1 No abnormality (i.e. normal) on ADC and high b‐value DWI
2 Indistinct hypointense on ADC
3 Focal mildly/moderately hypointense on ADC and isointense/mildly hyperintense on high b‐value DWI.
4 Focal markedly hypontense on ADC and markedly hyperintense on high b‐value DWI; <1.5cm in greatest dimension
5 Same as 4 but ≥1.5cm in greatest dimension or definiteextraprostatic extension/invasive behavior
T2 - Peripheral Zone
1 Uniform hyperintense signal intensity (normal)
2 Linear or wedge‐shaped hypointensity or diffuse mild hypointensity, usually indistinct margin
3 Heterogeneous signal intensity or non‐circumscribed, rounded, moderate hypointensityIncludes others that do not qualify as 2, 4, or 5
4 Circumscribed, homogenous moderate hypointensefocus/mass confined to prostate and <1.5 cm in greatest dimension
5 Same as 4 but ≥1.5cm in greatest dimension or definite extraprostatic extension/invasive behavior
DWI – PZ and TZ
1 No abnormality (i.e. normal) on ADC and high b‐value DWI
2 Indistinct hypointense on ADC
3 Focal mildly/moderately hypointense on ADC and isointense/mildly hyperintense on high b‐value DWI.
4 Focal markedly hypontense on ADC and markedly hyperintense on high b‐value DWI; <1.5cm in greatest dimension
5 Same as 4 but ≥1.5cm in greatest dimension or definiteextraprostatic extension/invasive behavior
DCE – Peripheral and Transition Zone
(-) no early enhancement, or
diffuse enhancement not corresponding to a focal
finding on T2
and/or DWI or
focal enhancement corresponding to a lesion
demonstrating features of BPH on T2WI
(+) focal, and;
earlier than or contemporaneously with enhancement
of adjacent normal prostatic tissues, and;
corresponds to suspicious finding on T2W and/or DWI
Overall Peripheral Zone
DWI T2 DCE PIRADS
1 Any Any 1
2 Any Any 2
3 Any - 3
+ 4
4 Any Any 4
5 Any Any 5
Overall Transition Zone
T2 DWI DCE PIRADS
1 Any Any 1
2 Any Any 2
3 <4 Any 3
5 Any 4
4 Any Any 4
5 Any Any 5
Correlation between PI-RADS and cancer
Will all patients with suspicion of prostate cancer undergo multiparametric MRI
before biopsy in the future?
Patients with no history of PCa
Patients with no history of PCaCONCLUSIONS
1. higher detection rate of clinicallysignificant PCa compared to systematicbiopsy (sensitivity of 0.91 versus 0.76 ) anda lower rate of detection of insignificantPCa (sensitivity of 0.44 versus 0.83 ).
2. the added value of TBx in detectingclinically significant PCa was marked in thesubgroup of patients with previousnegative biopsies (relative sensitivity of1.54) but not in the subgroup of biopsynaïve patients (relative sensitivity of 1.10).
Patients with no history of PCampMRI fusion TB does not significantly improve detection of CSPC in this setting◦ Men X (Taneja S) et al, Eur Urol 2015, Schoots et al, Eur Urol 2015, Finelli (CCO
systematic review 2015)
False positive rate of 17%◦ Bains et al, J Urol 2014
Reminiscent of the screening enthusiasm associated with the introduction of PSA?
The impact of tumor volume and multi-focalityOverall mpMRI sensitivity for tumor detection was 47% (132/283) with increased sensitivity for◦ Larger (102/141 [72%]>1.0 cm),
◦ Higher-grade (96/134 [72%] Gleason 7 tumors), and
◦ Index tumors (98/122 [80%]).
Potential tools of Targeted PBx
Initial biopsy◦ Reduce false negatives
◦ Improve risk classification
◦ Reduce repeat biopsies
◦ Reduce overdetection
Repeated biopsy◦ Increase cancer detection
◦ Reduce further repeat biopsy
In Active surveillance◦ Improve risk stratification
◦ Reduce need for repeat biopsy
Will all patients with suspicion of prostate cancer undergo multiparametric MRI before biopsy in the
future? mpMRI could be used in two different ways before biopsy:
Selection of patients who should undergo biopsy◦ Reduce the number of negative and unnecessary biopsies
Triggering targeted and systematic biopsies
Magnetic Resonance Imaging Before Prostate Biopsy: Time to Talk
Molecular targets for PCa PET-Imaging
PSMA as target for PCa-ImagingProstate Specific Membrane Antigen
Glutamate Carboxypeptidase II
1. Cell surface protein
2. Overexpression on most PCa Cells
3. Promising target for imaging and therapy
4. Development of various ligands
PSMA inhibitors
68-Ga-PSMA PET: physiological distribution
68-Ga-PSMA for Primary staging
68-Ga-PSMA for Primary staging (ctd)
68-Ga-PSMA PET for staging recurrent PCa
68-Ga-PSMA PET CT vs MR in recurrent PCa
68-Ga-PSMA PET vs morphological imaging
Influence of PSAdt and PSAvel on detection rate
68-Ga-PSMA PET: detection rate in recurrent PCA
18F-fluoromethylcholine PET vs 68-Ga-PSMA-PET
18F-fluoromethylcholine PET vs 68-Ga-PSMA-PET (ctd)
68-Ga-PSMA PET vs choline PET
68 Ga-PSMA PET and PSAHigh detection rate compared to conventional imaging modalities, especially in lower range PSA levels (Paffen EAU 16 #561)
Cut-off values (Cromphout EAU 16 #565)◦ PSA Cut-off value of 0.45 ng/ml
◦ If PSA <0.45, consider PSAdt < 5 months to perform PSMA
PSA <0.2 0.2-0.5 0.5-1 1-2 2-10 >10
Detectionrate
17% 38% 63% 75% 86% 100%
PSAdt < 3 mo 3-6 mo > 6 mo
Detection rate 87% 68% 65%
68-Ga-PSMA PET: all-inclusive?
New salvage options facilitated by 68-Ga-PSMA PET
Targeted salvage radiation therapy
PSMA radio-guided surgery
PSMA radio-guided surgery
Pitfalls of 68-Ga-PSMA
Pitfalls of 68-Ga-PSMA (Ctd)
Pitfalls of 68-Ga-PSMA (Ctd)
Potential indications for 68-Ga-PSMA PETBenefit using 68Ga-PSMA ligand PET/CT Patient group
High estimated benefit/diagnostic gain• Primary staging in high-risk disease according to D’Amico classification• Biochemical recurrence with low PSA-values (0.2 ng/ml to 10 ng/ml)a
Low estimated benefit/diagnostic gain• Primary staging in low-risk (and intermediate-risk) disease according to D’Amico classification
Potential application with promising preliminary data
• Biopsy targeting after previous negative biopsy, but high suspicion of PC (esp. in combination with multiparametric MRI using PET/MRI)
Potential application with current lack of published data
• Monitoring of systemic treatment in metastatic CRPCb
• Monitoring of systemic treatment in metastatic castration-sensitive PCb
• Active surveillance (esp. in combination with multiparametric MRI using PET/MRI)• Treatment monitoring in metastatic castration-resistant PC undergoing radioligand therapy targeting PSMA (e.g. 177Lu-PSMA-ligand)
ain biochemical recurrence with PSA-values over 10 ng/ml conventional imaging (e.g. CT, MRI, bone scan) is also able to demonstrate distribution of disease. Furthermore, at PSA-values > 10 ng/ml salvage options
facilitated by 68Ga-PSMA ligand PET/CT are unlikelybMonitoring of treatment in metastasized PC patients might be enhanced due to often limited applicability of RECIST 1.1 criteria (e.g. non-target lymph node/bone metastases without extra-osseous extension) and the
ineffectiveness of bone scan to reliably proving therapy response (e.g. flare phenomenon) compared to preclinical data suggesting PSMA-expression as indicator for response assessment
But nowadays every single house has more than one PC!
Thank you!Any questions??
Questions10 questions are presented hereby
One answer is valid for each question
All questions were obtained from the archives of the EU-ACME website
Question 1: Multiparametric MRI is a combination of imaging techniques that is used in the diagnosis of prostate cancer. Which of the following sequences gives a good anatomic picture of the prostate but is not sensitive enough to detect prostate cancer alone?
A. Diffusion weighted imaging
B. T2 weighted imaging
C. T3 weighted imaging
D. Dynamic contrast enhanced imaging
Question 2: One of the reasons why multiparametric MRI of the prostate is a promising tool in screening for prostate cancer is a high
A. Negative predictive value of significant prostate cancer
B. Sensitivity of insignificant prostate cancers
C. Positive predictive value for significant prostate cancer
D. Negative predictive value for insignificant prostate cancer
Question 3: Regarding detection of clinically significant prostate cancer, the following is correct:
A. MRI-TRUS targeted biopsy is consistently superior to standard TRUS biopsy across almost all studies
B. Standard TRUS biopsy is consistently superior to MRI-TRUS targeted biopsy across almost all studies
C. MRI-TRUS targeted biopsy and standard TRUS biopsy are equal across all studies
D. The combination of MRI-TRUS targeted biopsy and standard TRUS biopsy is the best modality across all studies
Question 4: A well known problem/s with TRUS guided systematic biopsies of the prostate following an elevated PSA areA. that cancers can not be seen on TRUS
B. that TRUS biopsies cause cancer to spread
C. generally low patient tolerability to the procedure
D. over- as well as underdiagnosis of prostate cancer
Question 5: Whick kind of radionuclide can be used for rabiolabeling PSMA?A. 64Cu, 68Ga, 223Ra
B. 64Cu, 18F, 153Sm, 131I
C. 64Cu, 18F, 68Ga and 223Ra
D. 64Cu, 89Zr, 18F and 68Ga
Question 6: What is the detection rate of 68Ga-PSMA in case of a PSA< 1 ng/ml? A. <20%
B. 20-30%
C. >60%
D. 15-45%
Question 7: Which statement is correct? Prostate-specific membrane antigen (PSMA) is
A. overexpressed in higher grade, metastasized or castration resistant prostate cancer cells.
B. is exclusively expressed in prostate cancer tissue only.
C. is never expressed in benign prostate tissue.
D. shows no expression under androgen deprivation therapy.
Question 8: Which statement is correct about 68Ga-PSMA PET/CT scanning?
A. 68Ga-PSMA PET/CT scan is an extensively validated standardized morphologic imaging method.
B. The binding affinity of the 68Ga-PSMA ligand allows to identify hormonsensitive prostate cancer cells only.
C. 68Ga-PSMA PET/CT can be used to detect intraprostatic lesions, as well as lymph node metastases, bone and visceral metastases.
D. Currently, imaging with 68Ga-PSMA can only be applied as PET-CT, and not in combination with another imaging method (e.g. PET-MRI).
Question 9: Which statement is correct about 68Ga-PSMA PET/CT scanning?
A. In presence of biopsy proven prostate cancer, PSMA is always positive in primary prostate cancer (particularly in absence of any prior therapy).
B. To date, 68Ga-PSMA PET/CT scanning seems to be highly specific for detection of prostate cancer, but reports about sensitivity revealed a great variation, especially in different clinical settings.
C. Currently, the detection rate of lymph node metastases, detected by 68Ga-PSMA PET/CT, is independent of histologic lymph node metastases size.
D. A specific cut-off standardized uptake value 68Ga-PSMA (SUV) allows to distinguish precisely between malignant tissue vs. non-malignant tissue.
Question 10: Which statement is correct?
A. PSMA is a validated alternative to PSA as serum-based prostate cancer marker for monitoring purpose in androgen deprived patients.
B. The combination of molecular imaging by 68Ga-PSMA with conventional morphologic imaging is only possible with CT and not with MRI.
C. Due to its binding mechanism the PET tracer 68Ga-PSMA is more specific than historical tracers such as choline or FDG based tracers.
D. Functional imaging by 68Ga-PSMA PET/CT is based on changed metabolism in prostate cancer cells (e.g. such as glucose or lipid)
Answers
Question 1: Multiparametric MRI is a combination of imaging techniques that is used in the diagnosis of prostate cancer. Which of the following sequences gives a good anatomic picture of the prostate but is not sensitive enough to detect prostate cancer alone?
A. Diffusion weighted imaging
B. T2 weighted imaging
C. T3 weighted imaging
D. Dynamic contrast enhanced imaging
T2 weighted imaging gives good anatomic information but BPH, scarring and other benign conditions can mimic cancer on T2. Therefore, T2 should be interpreted with functional techniques for optimal detection of prostate cancer[8].
Question 2: One of the reasons why multiparametric MRI of the prostate is a promising tool in screening for prostate cancer is a high
A. Negative predictive value of significant prostate cancer
B. Sensitivity of insignificant prostate cancers
C. Positive predictive value for significant prostate cancer
D. Negative predictive value for insignificant prostate cancer
Studies on the accuracy of multiarametric MRI for detecting significant prostate cancer has show high negative predictive values for significant prostate cancer[5, 6] . The negative predictive value is important because multiparametric MRI can be used to rule out significant cancer. It can be used to exempt men from systematic biopsies which in turn leads to reduced overdiagnosis of insignificant prostate cancer (which is the main drawback of today´s PSA-screening).
Question 3: Regarding detection of clinically significant prostate cancer, the following is correct:
A. MRI-TRUS targeted biopsy is consistently superior to standard TRUS biopsy across almost all studies
B. Standard TRUS biopsy is consistently superior to MRI-TRUS targeted biopsy across almost all studies
C. MRI-TRUS targeted biopsy and standard TRUS biopsy are equal across all studies
D. The combination of MRI-TRUS targeted biopsy and standard TRUS biopsy is the best modality across all studies
In all studies in which both detection rates were reported, the median absolute difference was at 6.8% with an overall range between 0.9% and 41.4%, always in favour of the software-based approach.
Question 4: A well known problem/s with TRUS guided systematic biopsies of the prostate following an elevated PSA areA. that cancers can not be seen on TRUS
B. that TRUS biopsies cause cancer to spread
C. generally low patient tolerability to the procedure
D. over- as well as underdiagnosis of prostate cancer
PSA has a low specificity and can be elevated due to several reasons. Many men with BPH undergo biopsies and since there is a large gap between “latent” prevalent prostate cancer and clinical prostate cancers, the systematic biopsies in men with elevated PSA frequently detects small, insignificant “latent” cancers (overdiagnosis). At the same time, PSA at the common cut-offs followed by systematic biopsies may miss significant cancers (underdiagnosis) [4]
Question 5: Whick kind of radionuclide can be used for rabiolabeling PSMA?A. 64Cu, 68Ga, 223Ra
B. 64Cu, 18F, 153Sm, 131I
C. 64Cu, 18F, 68Ga and 223Ra
D. 64Cu, 89Zr, 18F and 68Ga
Considerations: a lot of radionuclide have been used for radiolabeling PSMA. First experimental studies were performed by using 89Zrand 64Cu, but for the unfavorable physical characteristics they were replaced by 68Ga and 18F..
Question 6: What is the detection rate of 68Ga-PSMA in case of a PSA< 1 ng/ml? A. <20%
B. 20-30%
C. >60%
D. 15-45%
Considerations. The main advantage of 68Ga-PSMA as compared to radiolabeled choline PET/CT is the ability to detect recurrent prostate cancer in case of very low PSA level (<1 ng/mL). References: 1. Afshar-OromiehA, Avtzi E, Giesel FL, et al. The diagnostic value of PET/CT imaging with the 68Ga-labelled PSMA ligand HBED-CC in the diagnosis of recurrent prostate cancer. Eur J Nucl Med Mol Imaging 2015;42:197–209
Question 7: Which statement is correct? Prostate-specific membrane antigen (PSMA) is
A. overexpressed in higher grade, metastasized or castration resistant prostate cancer cells.
B. is exclusively expressed in prostate cancer tissue only.
C. is never expressed in benign prostate tissue.
D. shows no expression under androgen deprivation therapy.
This was histologically validated in several independent, previous series, before implementation of 68Ga-PSMA PET/CT. About 2B, there are is prostate unrelated tissue, such as salivary glands or paraganglia, mimicking the uptake of prostate cancer tissue
Question 8: Which statement is correct about 68Ga-PSMA PET/CT scanning?
A. 68Ga-PSMA PET/CT scan is an extensively validated standardized morphologic imaging method.
B. The binding affinity of the 68Ga-PSMA ligand allows to identify hormonsensitive prostate cancer cells only.
C. 68Ga-PSMA PET/CT can be used to detect intraprostatic lesions, as well as lymph node metastases, bone and visceral metastases.
D. Currently, imaging with 68Ga-PSMA can only be applied as PET-CT, and not in combination with another imaging method (e.g. PET-MRI).
This is shown in the current study and in several citied references, e.g. [2]. About 2D), a recent publication by Eiber et. al. [3] reports about 68Ga-PSMA HBED-CC PET/MRI. About 2A), there are different protocols with regard to ligands used, radiotracer dosage and imaging protocols.
Question 9: Which statement is correct about 68Ga-PSMA PET/CT scanning?
A. In presence of biopsy proven prostate cancer, PSMA is always positive in primary prostate cancer (particularly in absence of any prior therapy).
B. To date, 68Ga-PSMA PET/CT scanning seems to be highly specific for detection of prostate cancer, but reports about sensitivity revealed a great variation, especially in different clinical settings.
C. Currently, the detection rate of lymph node metastases, detected by 68Ga-PSMA PET/CT, is independent of histologic lymph node metastases size.
D. A specific cut-off standardized uptake value 68Ga-PSMA (SUV) allows to distinguish precisely between malignant tissue vs. non-malignant tissue.
Variation in detection rates might be also due to the aspect of histological validation. In the current study, histological validation of PSMA positive lesions was performed, further studies with similar approaches are pending and needed.
Question 10: Which statement is correct?
A. PSMA is a validated alternative to PSA as serum-based prostate cancer marker for monitoring purpose in androgen deprived patients.
B. The combination of molecular imaging by 68Ga-PSMA with conventional morphologic imaging is only possible with CT and not with MRI.
C. Due to its binding mechanism the PET tracer 68Ga-PSMA is more specific than historical tracers such as choline or FDG based tracers.
D. Functional imaging by 68Ga-PSMA PET/CT is based on changed metabolism in prostate cancer cells (e.g. such as glucose or lipid)
Due to is binding mechanism and the prostate cancer specific expression pattern with relative PSMA overexpression, 68Ga-PSMA ligands are targeting prostate cancer more specific than metabolism based ligands
