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Rationale for Modernising Imaging in Advanced Prostate Cancer
Eur Urol Focus, 2016 doi: 10.1016/j.euf.2016.06.018<http://dx.doi.org/10.1016/j.euf.2016.06.018> [Epub ahead of print]
To effectively manage patients with advanced prostate cancer (APC), it is essential to have accurate, reproducible, and validated methods for detecting and quantifying the burden of bone and soft tissue metastases and for assessing their response to therapy. Current standard of care imaging with bone and computed tomography (CT) scans have significant limitations for the assessment of bone metastases in particular.
We aimed to undertake a critical comparative review of imaging methods used for diagnosis and disease monitoring of metastatic APC from the perspective of their availability and ability to assess disease presence, extent, and response of bone and soft tissue disease.
An expert panel of radiologists, nuclear medicine physicians, and medical physicists with the greatest experience of imaging in advanced prostate cancer prepared a review of the practicalities, performance, merits, and limitations of currently available imaging methods.
Meta-analyses showed that positron emission tomography (PET)/CT with different radiotracers and whole-body magnetic resonance imaging (WB-MRI) are more accurate for bone lesion detection than CT and bone scans (BSs). At a patient level, the pooled sensitivities for bone disease by using choline (CH)–PET/CT, WB-MRI, and BS were 91% (95% confidence interval [CI], 83–96%), 97% (95% CI, 91–99%), and 79% (95% CI, 73–83%), respectively. The pooled specificities for bone metastases detection using CH-PET/CT, WB-MRI, and BS were 99% (95% CI, 93–100%), 95% (95% CI, 90–97%), and 82% (95% CI, 78–85%), respectively. The ability of PET/CT and WB-MRI to assess therapeutic benefits is promising but has not been comprehensively evaluated. There is variability in the cost, availability, and quality of PET/CT and WB-MRI.
Standardisation of acquisition, interpretation, and reporting of WB-MRI and PET/CT scans is required to assess the performance of these techniques in clinical trials of treatment approaches in APC.
PET/CT and whole-body MRI scans have the potential to improve detection and to assess response to treatment of all states of advanced prostate cancer. Consensus recommendations on quality standards, interpretation, and reporting are needed but will require validation in clinical trials of established and new treatment approaches.
Keywords: Advanced prostate cancer, Metastatic castrate-resistant prostate cancer, Bone scans, PET/CT scans, Whole-body MRI, Diffusion MRI, Response assessment, Metastasis detection.
Advanced prostate cancer (APC) patients who present with metastatic disease at the time of diagnosis or after failed attempts at curative therapy almost always respond to androgen deprivation therapy (ADT). However, ADT initiation inevitably leads to the development of the castration-resistant disease state, which occurs within 1–3 yr in most patients  and . More than 80% of patients with metastatic castrate-resistant prostate cancer (mCRPC) have bone metastases, which produce significant morbidity and are associated with increased mortality , , and . Data from older studies suggest that overall survival (OS) is approximately 30–36 mo from the appearance of metastases, with a median OS of approximately 18 mo once the metastatic castrate-resistant state is established , , and . More contemporary data confirm that OS remains poor, approximately 30–42 mo , , and , even with the increased number of active treatments available for mCRPC. These data emphasise the continued need for improvements in the diagnosis and treatment of APC.
With the increasing availability of therapies that prolong survival for metastatic castrate-naive prostate cancer (PCa) and mCRPC and the increasing use of prostate-specific antigen (PSA) testing after definitive therapy, imaging detection of the metastatic state is occurring for lower disease burdens. Recent data on patients who developed metastatic disease indicated that most have bone-only disease (62%), with bone and soft tissue metastases occurring in an additional 12% . Soft tissue metastases occur mostly in lymph nodes outside the true pelvis, possibly because many patients receive pelvic radiotherapy for biochemical recurrence (BCR). Visceral metastases (liver, lungs, and other sites) occur infrequently at initial relapse (2%) , but prevalence increases with advancing disease (15–21% in mCRPC)  and . The prevalence of visceral metastases also increases after multiple lines of treatment and with the emergence of aggressive histologic variants; antemortem, visceral disease can be observed in up to half of the patients .
APC patients with bone metastases have a greater risk of skeletal morbidity, which can impair quality of life (QoL) . Bone disease causes pain, pathologic fractures, hypercalcaemia, anaemia, and spinal cord and nerve compression. Delaying symptoms from bone metastases as APC progresses is central to therapeutic management . Treatments for bone metastases are generally systemic but often include local radiotherapy and/or surgery; all are currently given with palliative intent. The treatment of APC with bone metastases has significant health economic implications including the costs of systemic therapy (endocrine therapy, chemotherapy, radioisotope treatments, bisphosphonates, other supportive care medications); imaging; hospital admissions for the treatment of fractures, hypercalcaemia, and cord compression; and the costs of palliative radiotherapy  and .
To effectively manage patients with metastatic disease, it is essential to have accurate, reproducible, and validated methods for detecting and assessing response to therapy. These methods include clinical reviews, the use of serum PSA as a tumour marker, circulating tumour cell counts, blood and urinary markers of bone health, and imaging assessments  and .
1.1. Need for comprehensive metastatic imaging assessments
Imaging helps define the clinical groups for drug development  and clarifies the APC state for therapy recommendations  because the presence, volume, and distribution of metastatic disease has profound implications for the curability of PCa, greatly affecting therapy choices. At initial staging or in the setting of initial BCR, for example, the presence of metastatic disease often precludes the use of curative and local salvage options. The time to metastasis development in BCR is also highly prognostic, with a shorter interval to radiographically depicted metastasis associated with poor OS . The presence and volume of metastatic skeletal disease is also highly prognostic, regardless of the imaging method used for metastatic volume estimation , , , , and .
Imaging can also identify patients with metastatic disease patterns who have poorer prognosis. Subgroup analysis of major clinical trials has shown that imaging features contribute strongly to prognostic models that predict for survival for docetaxel-treated patients . In mCRPC, the location of metastases, particularly the presence of visceral disease and the number of skeletal metastases, are highly prognostic , , , and . A recent meta-analysis showed varying OS according to the anatomic location of metastases in men with mCRPC treated with docetaxel, with increased lethality for lung and liver metastases compared with bone and lymph nodal involvement .
Patients with poorer prognosis and higher tumour volumes appear to benefit from intensified combination treatments , , and . In the CHAARTED study, “high volume” disease was defined by the imaging presence of visceral disease and/or more than four bone metastases with at least one metastasis beyond vertebral bodies or the pelvic skeleton . In mCRPC, the presence of visceral or symptomatic disease is often used as a reason for initiating chemotherapy in fit patients  and .
Patients are deemed to have “anaplastic features” based on clinical, biochemical, or imaging results. Imaging features used include exclusively visceral or predominantly lytic bone metastases, bulky tumour masses, low PSA levels relative to tumour burden, and short responses to ADT. Patients defined in this way may benefit more from combination docetaxel and platinum chemotherapy compared with docetaxel alone , although this remains controversial.
Well-powered clinical studies have shown that that abiraterone and enzalutamide therapy of asymptomatic or mildly symptomatic chemotherapy-naive mCRPC patients can be helpful for delaying clinical decline and death  and . In this group, lower volume disease such as fewer than four bone metastases  and better performance status  and  seem to indicate improved OS. Note, however, that the presence of visceral disease and/or large-volume nodal metastases also precludes the use of some treatments such as the alpha particle emitter radium 223 .
Finally, the duration of imaging responses is also reported to be highly prognostic. No response or shorter durations of response to abiraterone and docetaxel treatments using bone scans (BSs) and the size-based criteria (for soft tissue disease) are associated with worse OS  and . These poorer prognosis patients, failing androgen axis–targeted therapies, may benefit from earlier treatment with nontargeted survival-prolonging combination therapies such as docetaxel and cabazitaxel while still asymptomatic, although this too remains controversial.
These data, taken together, emphasise the need for improved precision in evaluating the metastatic status of APC patients, as baseline imaging characteristics can influence therapy choices. Furthermore, these data suggest a need for the detection of metastases when disease load is lower and for more accurate readouts of therapy benefits (to detect primary and secondary resistance) to enable individualised treatment approaches to be investigated.
2. Evidence acquisition
2.1. Search strategy and selection criteria
At the 2015 St. Gallen Advanced Prostate Cancer Consensus Conference (APCCC), most oncologic experts accepted that novel imaging techniques (positron emission tomography [PET]/computed tomography [CT] with different radiotracers and whole-body magnetic resonance imaging [WB-MRI]) are more accurate for lesion detection than conventional imaging with CT and BSs . However, panel members noted that there was considerable variability in the cost, availability, and quality of these imaging modalities. Following the APCCC meeting, an expert panel of radiologists with the largest experience of imaging in APC convened to review the performance merits and limitations of currently used imaging methods. We searched for articles in PubMed on APC and metastatic disease, focusing on detection and response assessments between 2000 and 2015. Although the focus was on imaging metastatic PCa, other tumour types with major malignant bone involvement, including myeloma and breast cancer papers, were also evaluated for relevant data. All papers identified were in the English language and were original scientific papers and review articles. We also searched the references listed for additional relevant papers and conference proceedings. As part of the imaging review, guidelines were formulated on the performance, quality standards, interpretation, and reporting of WB-MRI for the assessment of APC; see the accompanying Metastasis Reporting and Data System–Prostate (MET-RADS-P) publication for the guideline .
2.2. Biology of bone disease relevant for imaging
The molecular processes driving PCa cell metastasis to the bone are beginning to be understood , , and . In bone, PCa cells mostly cause osteoblastic lesions via the secretion of paracrine factors that stimulate osteoblasts recruitment and function, thereby leading to excess bone formation. Osteoclastic activation at the margins allow metastases to enlarge; the latter mechanism may become dominant in late-state disease. Tumour-matrix interactions affect the imaging phenotype; these interactions are summarised in Supplement 1.
2.3. Current use of imaging in advanced prostate cancer management
The current use of imaging in APC was surveyed at the 2015 St. Gallen APCCC . An international expert consensus panel consisting of PCa specialists who were involved in patient care undertook panel discussions and voted on predefined questions on the use of imaging. While continuing to emphasise the use of bone and CT scans, the APCCC panellists highlighted the need to evaluate newer imaging modalities for early diagnosis and treatment monitoring and to assess their impact on patient outcomes. The APCCC discussions on the current use of imaging in APC are summarised in Supplement 2.
2.4. Comparison of imaging technologies for metastatic disease assessments
Radiologic approaches for metastatic evaluations have specific advantages, including their disease manifestation–specific depiction ability (ie, ability to separately assess prostate, bone, nodal, and visceral disease), noninvasive nature, documentation capability, variable ability for whole-body imaging, resolution flexibility (submillimetre to subcentimetre), ability to depict physiologic and molecular processes within and between lesions and patients, and ability to assess spatial heterogeneity of disease distribution and response. Comprehensive reviews of imaging methods for APC can be found in the literature, and all point out that microscopic metastasis depiction cannot be comprehensively undertaken by any external imaging methods  and . In this review, we only comment on commonly used imaging techniques in the setting of APC, focusing on metastasis detection abilities and response assessment capabilities. In Table 1, we summarised the advantages and limitations of imaging techniques, focusing on the partialities of usage.
Summary of the advantages and limitations of whole-body imaging methods suited for advanced prostate cancer evaluations
|CT scan||• Widely available
• Easily standardised
• Low cost
• Fast acquisition
• Quantitative assessments (Hounsfield unit)
• Ability to characterise bone disease into the spectrum between sclerotic and lytic
• Soft tissue and lytic bone metastasis detection and response assessments
• Incorporated into clinical practice and trial guidelines
|• Does not directly evaluate malignant bone disease when soft tissue is absent
• Radiation exposure
• Limited local disease evaluations
• Subcentimetre nodal characterisation
• Cannot visualise infiltrative (nonsclerotic) bone disease
• CT “flare” response
• Inability to diagnose response/progression in sclerotic bone metastases
|• Complementary to PET or whole-body MRI information
• Sclerotic change in nonsclerotic lesions as potential response parameter
• Lung metastases detection
• Lytic vs nonlytic bone metastases subclassification
|Bone scan||• Widely available
• Easily standardised
• Low cost
• Incorporated into clinical practice and trial guidelines
|• Does not directly evaluate malignant bone disease; reactive osteoblastic uptake only
• Longest examination times
• Pre- and postexamination care precautions
• Radiation exposure to patients and public due to longer half-life of technetium Tc 99m
• No ability to assess soft tissue disease
• Lower sensitivity and specificity than CT/MRI
• Bone scan flare response
• No positive benefit criteria (progression only)
|• Improved test performance by addition of SPECT/CT capability
Development of bone scan index as prognostic biomarker
|Sodium fluoride PET/CT||• High sensitivity and relatively good specificity for bone metastases (CT component adds specificity)
Medium-length examination times
|• Does not directly evaluate malignant bone disease; reactive osteoblastic uptake only
• Limited tracer availability
• Multiple sources of radiation exposure (CT scans and radiotracer)
• Some postexamination care precautions (not burdensome)
• Limited ability to assess soft tissue disease related to the lower quality of the CT component; used for attenuation correction
• Flare response phenomenon
• No positive benefit criteria (progression only)
|• Development of NaF tumour volume index as prognostic biomarker|
|Choline PET/CT||• Directly evaluates malignant bone marrow disease
• High sensitivity and relatively good specificity for detection of bone and soft tissue metastases
• Ability to assess response of bone and soft tissue disease
• Objective response parameters (SUV)
Medium-length examination times
|• Limited tracer availability
• Multiple sources of radiation exposure (CT scans and 18F-CH radiotracer. less so for 11C-CH due to shorter half-life)
• Some postexamination care precautions (not burdensome)
• Potential to be influenced by bone marrow–stimulating factors
• Inability to accurately assess liver and urinary lesions
|• Development of SUV as a potential response biomarker
• Development of tumour load as a prognostic biomarker
|Whole-body MRI||• Directly evaluates malignant bone marrow disease
• Potential wide availability
Lack of radiation
• Flexible, adaptable imaging (possible to tailor examinations according to disease location)
• Ability to detect and assess response of bone and soft tissue disease including the prostate, nodes, and viscera
• Objective response parameters (size, volume, and ADC measurements)
|• Competing demands for MRI resource
• Scanner-dependent performance
• Longer acquisition time
• Susceptible to artefacts
• Subcentimetre nodal and lung metastases detection and characterisation ability
• Influenced by bone marrow–stimulating factors and blood transfusions
• Limited radiologic expertise in some aspects of image analysis
• Data analysis challenges
• Higher cost (equal to combined bone and CT scans) and reimbursement challenges
|• Radiation-free long-term follow-up
• Surgical planning
• Skeletal event detection (spinal cord compression, critical fractures)
• “One stop-shop”: bone and soft tissue disease detection and response assessments
ADC = advanced prostate cancer; CH = choline; CT = computed tomography; MRI = magnetic resonance imaging; PET = positron emission tomography; SPECT = single-photon emission computed tomography; SUV = specific uptake values.
2.4.1. Bone scans
Currently, BSs are the mainstay of bone metastatic disease evaluations, including modern extensions such as single-photon emission CT (SPECT) and SPECT-CT . It is important to remember that the uptake of technetium Tc 99m bone-binding radiotracers is related to osteoblastic activity and does not necessarily reflect the full burden of disease within the marrow space (Fig. 1). Compared with modern imaging methods such as choline (CH)–PET/CT and WB-MRI scans, BSs are inferior in terms of lesion detection ability, as discussed in section 3, “Evidence synthesis”  and .
Multiregional whole-body magnetic resonance imaging (WB-MRI) capability. Clinical details: A man aged 74 yr with high-risk prostate cancer (prostate-specific antigen 37.5 ng/m; Gleason 4 + 4; five of nine cores positive on the left side only). Clinical question: query local and metastatic staging. (a) Dedicated multiparametric prostate MRI (b value of 750 s/mm2 [b750], apparent diffusion coefficient map, T2-weighted images in the axial and coronal plane) were undertaken using a 1.5-T scanner. There is a large 4-cm left apical mass bulging the prostatic capsule in the region of the left neurovascular bundle, indicating T3a disease (arrows). (b) Planar (anterior and posterior views) and single-photon emission computed tomography (sagittal and axial sections) bone scans showing the presence of a likely metastasis in the upper dorsal spine. Localisation to a specific vertebral body is difficult. No other lesions were detected. (c) A comprehensive WB-MRI protocol was undertaken using a 3-T scanner (note the higher signal intensity compared with the 1.5-T scanner images in Fig. 3–5 and Supplementary Fig. 2 and 4). Sagittal short tau inversion recovery (STIR) and maximum-intensity projection images (anteroposterior projection and right shoulder forward, oblique) all show a metastasis in the T4 vertebral body (arrow). The lower signal in centre of the lesion on the STIR image is consistent with mineralisation. There is osteoporotic loss of vertebral height at T3. The primary tumour at the left prostatic apex is also visible (arrows). (d) (left column) B value of 900 s/mm2 (b900) diffusion-weighted and (right column) T1-weighted fat-fraction images confirm the presence of the metastasis at T3 (top row; arrow). Further metastases are seen at L5 (middle row; arrow), and multiple smaller lesions are in the left posterior iliac bone (bottom row; arrows). Note the lower lesion contrast on the diffusion-weighted b900 images of the L5 and iliac bone lesions.
ADC = apparent diffusion coefficient; AP = anteroposterior; b750 = b value of 750 s/mm2; b900 = b value of 900 s/mm2; STIR = short tau inversion recovery; TW1 = T1 weighted; T2W = T2 weighted.
BS evaluations of therapy response are also indirect, with sensitivity for disease progression only in most cases. Among the major limitations of BS when assessing therapy effects is the possibility of a “flare” reaction when BSs are performed within 8–12 wk of treatment initiation (flare is defined as the development of new lesions on a first follow-up scan that actually represent a favourable response to treatment on longer term observations  and ; the enlargement of previously detected lesions is currently excluded from the definition of the flare reaction in pharmaceutical trials). Such flare reactions can occur in up to 15% of mCRPC patients treated with abiraterone . These flare reactions can lead to diagnostic confusion (pseudoprogression vs true progression) and can result in incorrect management changes . To take into account the possibility of early flare reactions, the Prostate Cancer Clinical Trials Working Group (PCWG) suggested that all patients that have at least two new lesions on the first follow-up BS require a confirmatory BS to be performed after >6 wk while treatment is continued  and ; BS progression is documented to have occurred only if two or more new lesions are seen on the confirmatory BS (2 +2 rule) . This means that management change for primary therapy resistance cannot occur until after at least 14 wk of treatment (depending on the reassessment schedule). Readers should also note that the emergence of two or more new lesions after the flare period only requires confirmation on a follow-up scan (ie, new lesions are not required); this strategy can also result in delays in changing therapy in the setting of secondary resistance.
We have already noted that BS progression criteria do not take in consideration increases in extent of preexisting lesions, relying only on the emergence of new lesions , further limiting the utility of BS to identify disease progression. Another important point to note is that the PCWG progression criteria described earlier cannot be applied to patients with diffuse metastatic bone disease BS uptake (“superscans”), as new disease cannot be identified on the background of diffusely elevated tracer uptake.
It should also be pointed out that the ability of BS to positively identify response (as opposed to stable or progressive disease) is also constrained because reductions of bone activity take a prolonged period of time to occur, limiting the timeliness of readouts. To date, the rapid resolution of BS is a phenomenon that is almost never observed among therapies known to confer survival benefit; therefore, BS reductions in activity should not be considered as a positive indicator of response. Rapid reductions in BS activity were shown in clinical trials of cabozantinib in APC (Supplementary Fig, 2) , but reductions of BS activity did not predict OS .
More recent advances in BS lesion quantification such as lesion area, the BS index, or lesion number , , , and  do not help overcome the limitations of the BS as a tool to identify therapy benefit. However, as already noted, disease load depicted on BS is highly prognostic , , and , and increases in quantitative BS index can be used to identify disease progression in therapy assessment settings  and .
To summarise, the clinical consequences of the limited performance of BS readouts when assessing response include (1) inability to diagnose primary and secondary treatment resistance rapidly, keeping patients on treatments from which they may gain no benefit for longer than necessary (overtreatment for nonresponding disease), (2) undertreatment when flare reactions are mistaken for disease progression in responding patients (pseudoprogression vs progression confusion), (3) undocumented increases in tumour burden (increase in extent but not number of bone lesions) while awaiting the emergence of new lesions on confirmatory BS (potentially disadvantaging patients regarding future clinical trials entry). In addition, many patients with bone superscans cannot be evaluated at all. For these reasons, in our opinion, the current evidence points away from the use of BSs for clinical practice when assessing response in bone disease. However, given the wide availability of BS and its acceptance in the oncologic community despite recognised limitations, the BS continues to be recommended, particularly for clinical trials , , , and .
2.4.2. Computed tomography
CT can directly evaluate metastatic disease, providing a means of detecting and measuring lesions, evaluating extent of disease involvement, and quantifying response to treatment of soft tissue disease. Consequently, CT scan measurements are incorporated into clinical care and clinical trials for disease detection and response assessment. It must be appreciated that size-based criteria are severely limited for metastatic nodal disease detection in PCa . However, there is considerable efficacy using CT-based size criteria for assessing therapy response of known soft disease, thus the incorporation of CT measurements into response assessment systems such the PCWG criteria and Response Evaluation Criteria In Solid Tumors (RECIST)  and .
CT scans also allow the structure of bone disease to be evaluated, enabling the primary classification of bone metastasis on a spectrum from lytic to sclerotic disease. The biological basis for the range of bone metastasis manifestations is discussed in detail in Supplement 1. It is important to note that patients with CT-depicted presence of predominantly lytic bone metastases associated with bulky soft tissue disease, including visceral disease (in patients with low PSA levels relative to tumour burden), should be considered to have anaplastic features. These patients may require biopsy with a view to reassessing the histologic phenotype and to intensive chemotherapy if anaplastic or neuroendocrine variants are found .
Some studies have shown that CT scans are superior to BSs for detecting lytic bone disease and in differentiating between sclerotic changes associated with malignancy versus degenerative disease. Consequently, CT serves as an aid to improve the test performance of BSs (SPECT/CT) and sodium fluoride PET scans (NaF-PET/CT). However, test performance for metastatic detection remains inferior to WB-MRI and PET/CT scans, especially for nonsclerotic, nonlytic bone metastases , as detailed in section 3, “Evidence synthesis.”
It is accepted that CT scans can be used to assess bone metastasis response to treatment in clinical trials but only when there is clearly measurable soft tissue disease , , and . However, the presence of measureable soft tissue occurs in only a minority of bone lesions , rendering many patients with bone disease ineligible for trial entry because there are no accepted bone tumour response criteria.
The development of bone sclerosis within metastatic lesions has been suggested as a method for assessing response for metastatic breast cancer within the MD Anderson Cancer Center criteria, provided that bisphosphonates are not used . These criteria recognise that bone structures rarely normalise with effective therapy and that the development of dense osteosclerosis of a lytic or mixed lytic/sclerotic lesion can be used as an indicator of therapy benefit because increased osteoblastic activity occurs as a healing response. However, no CT density thresholds have been established for distinguishing inactive bone metastases from active sclerotic metastases, although emerging data suggest that a well-defined bone lesion with homogenous increased CT density (>800–1000 Hounsfield units) can be relatively inactive when judged on CH-PET/CT scans . The CT flare phenomenon, defined as the emergence of a new bone lesion or a transformational change of an ill-defined sclerotic lesion into a dense, well-marginated bone lesion, has been described in 8% of APC patients and has been successfully treated . The development of new osteosclerotic lesions should not be classified as progression on its own unless there is other evidence of disease progression.
Taking the above discussion into considerations, we suggest that bone disease progression on CT can be identified by the unequivocal presence of new or enlarging soft tissue disease associated with bone lesions or by the rapid disappearance of sclerotic disease due to replacement by visible lytic disease. New sclerotic lesions by themselves do not constitute progression, particularly when dense or well defined. However, the emergence of new woven bone (milky or irregular appearance with ill-defined margins) in previously normal-appearing regions maybe considered as progression in the presence of consistent MRI/PET-depicted abnormalities and/or clinically worsening disease and in the absence of antiosteoclastic treatments (Fig. 2). We assert that early response of bone metastases on CT scans in the absence of extraosseous soft tissue disease cannot be identified but may be seen late when normal trabecular bone is restored.
Bone disease progression criteria. A man aged 74 yr with metastatic castrate-resistant prostate cancer was treated with abiraterone. Increasing symptoms with nausea and bone pain were accompanied by a rise in serum prostate-specific antigen. Computed tomography scans before and during treatment. Software straightening and vertebral body labelling of the lumbar spine was undertaken for illustration purposes. There is evidence of disease progression due to the presence of new woven bone (milky or irregular appearance with ill-defined margins) in previously normally appearing regions in the lumbar spine and sacrum with loss of height in several vertebrae.
PSA = prostate-specific antigen.
2.4.3. Positron emission tomography
Two PET radiotracers are widely used for imaging APC: the bone-seeking tracer fluorine F 18 (18F)–NaF, which, like 99mTc-MDP, acts as a more efficient marker of osteoblastic action; and the metabolic tracer carbon 11 (11C)/18F–CH, the uptake of which is partially related to membrane phospholipid synthesis  and . There are many other PET tracers, such as fluorodihydrotesterone (directed to the androgen receptor [AR]), gallium- and fluoride-labelled prostate-specific membrane antigen (PSMA), and F-fluciclovine (amino acid transportation; approved by the US Food and Drug Administration in 2016), that have variable geographic availability and for which assessment of clinical utility for disease detection and response in APC is ongoing . The more commonly used general oncology radiotracer fluorodeoxyglucose (FDG-PET/CT) is not often used in the evaluation of APC because of its low sensitivity for disease detection . However, it has been reported that in APC patients with FDG-avid metastases, the amount and extent of FDG-avid disease inversely correlate with survival .
CH-PET has potential advantages in displaying changes in metabolic activity that may occur prior to changes in CT-depicted morphology . CH-PET/CT scans are superior to BSs and CT scans for detecting bone disease, with performance equivalent to WB-MRI scans . CH-PET/CT performs poorly in the liver because there is high background hepatic uptake, limiting potential use for later stages of mCRPC, when there is an increased prevalence of metastatic liver disease . In addition, 18F-CH–PET/CT performs poorly in the evaluation of the urinary tract due to urinary excretion (not seen with 11C-CH). In contrast, CH-PET/CT performs better than WB-MRI in the assessment of lymph nodes  (Supplementary Fig. 3), although there are limitations in detecting microscopic disease in normally sized nodes at low serum PSA levels (<0.5–1.0 ng/ml in prostatectomy patients) . The ability of CH-PET/CT to assess response has not been systematically evaluated, but a few small studies have shown changes in disease extent and specific uptake values in response to treatment , , and  (Fig. 3). It should also be noted that the flare phenomenon (false increases in fluorocholine PET tracer uptake) can also be observed in responding bone lesion early after starting abiraterone .
Choline positron emission tomography (PET) to monitor response to chemotherapy. A man aged 57 yr with metastatic castrate-resistant prostate cancer. Fluorocholine PET scans (frontal projection, inverted scale). Note normal high radiotracer uptake in liver, kidneys, urinary bladder, pancreas, small bowel, salivary glands, and pituitary fossa. (Left panel) Status after abiraterone and docetaxel (prostate-specific antigen [PSA] 5.2 ng/ml) showing mediastinal (horizontal arrow) and retroperitoneal (slanting arrow). (Middle panel) After six cycles of cabazitaxel chemotherapy (PSA 3.2 ng/ml), the patient showed a good response with residual abnormalities. (Right panel) Extensive relapsed disease on follow-up (PSA 133 ng/ml) with extensive subdiaphragmatic nodal relapse together with left supraclavicular nodal disease (vertical down arrow). New metastasis in the left upper femur. Note fading of background bone marrow due to cell kill effects of chemotherapy.
Preliminary data suggested that PSMA-targeted N-(N-[(S)-1,3-dicarboxypropyl]carbamoyl)-4-18F-fluorobenzyl-l-cysteine (18F-DCFBC) PET/CT has improved performance compared with CT and BS for disease detection . Early data also suggested that the more frequently used gallium Ga 68 PSMA radiotracers have greater sensitivity for disease detection than CH-PET/CT in patients with BCR, especially at low PSA values, although test performance remains dependent on PSA levels , , and . The improved performance of PSMA-PET/CT compared with CH-PET/CT is possibly caused by lowered background activity in the bones and liver  and . The ability of PSMA-PET/CT to evaluate therapy response has not been systematically evaluated. In this context, it must also be remembered that PSMA expression is dependent on the AR status of PCa cells, and the way in which AR-directed treatments alter PSMA-PET/CT test sensitivity remains largely unexplored  and .
2.4.4. Magnetic resonance imaging
MRI can also directly evaluate metastatic disease, providing a means of detecting and measuring lesions, evaluating the extent of disease involvement, and quantifying response to treatment of both soft tissue and bone marrow disease. Consequently, MRI scan measurements are incorporated into clinical care and clinical trials for disease detection and response assessment, often as alternatives to CT scans. CT detection is superior for lung metastasis, but MRI performs better in detecting liver lesions. As with CT, size-based criteria severely limit metastatic nodal disease detection in PCa .
The key advantage of MRI is that bone marrow disease is directly evaluated. MRI sequences can be designed to be sensitive to different aspects of the marrow, such as marrow water and fat (using proton density–weighted, T1-weighted [T1W], T2-weighted [T2W], and short τ inversion recovery [STIR] sequences), the cellularity of the bone marrow (diffusion-weighted [DW] MRI), vascularity (dynamic contrast-enhanced MRI), trabecular bone (ultrashort echo time MRI and susceptibility weighted MRI), and bone marrow fat:water ratio (Dixon MRI, magnetic resonance spectroscopy). Importantly, techniques can be combined within the same examination to enable both morphologic and functional (including quantitative) assessments that can be repeated as often as required, as there is no radiation exposure penalty. Another advantage of MRI is the ability to perform disease-tailored multiregional studies focused on the bones, lymph nodes, viscera, and prostate gland (Fig. 1). A WB-MRI examination suitable for disease detection and response assessment can be performed in <1 h; practical WB-MRI sequence protocols can be found in the accompanying MET-RADS-P standards publication .
220.127.116.11. Morphologic magnetic resonance imaging scans
Morphologic T1W, T2W, and STIR images can be easily acquired on all MRI scanners without exception, and radiologic expertise for their interpretation is widely available  and . Morphologic sequences are key for the confident detection of new metastases until the time when diffuse disease occurs, after which the detection of disease reactivation becomes problematic. Morphologic criteria for bone disease progression and response are well described in the literature . Small studies in metastatic breast cancer have described morphologic MRI bone marrow changes in response to treatment  and . A study evaluating 109 MRI studies in advanced breast cancer found that it was possible to accurately predict progression in 79% of cases and stable disease in 75% of cases, but MRI could not predict regression of disease due to the limitations of morphologic sequences . Specific clinical data on the use of morphologic MRI in the routine assessment of metastatic bone disease response in APC are lacking . Tombal et al noted that there was an opportunity to measure bone disease using morphologic MRI sequences (disease that would otherwise be considered unmeasurable by RECIST) and, in so doing, to potentially double the proportion of APC patients who could be entered into clinical trials . This suggestion of RECIST-like criteria for bone disease assessment has not been widely taken up nor validated in clinical trials.
Morphologic MRI sequences that assess bone marrow response have a number of limitations, including arrested resolution of abnormalities despite effective therapy (the residual scar phenomenon, presumed to be due to bone sclerosis, marrow fibrosis, or tumour necrosis) . Another limitation is the problem of evaluating disease activity on a background of previously treated disease (ie, progression can be documented only by the emergence of new disease on previously uninvolved marrow). A T1W image pseudoprogression, the flare phenomenon, can also occur because of intense bone marrow oedema following tumour cell kill and inflammation. T1W flare is more likely to be associated with chemotherapy use and, locally, after radiation treatment, but its frequency is undocumented.
18.104.22.168. Diffusion-weighted images
The disease detection and response assessment performance of WB-MRI is enhanced by adding DW sequences , , and , which also help to overcome some of the limitations of morphologic sequences, described earlier. DW images depict the per-pixel averages (ie, at millimetre scale) of microscopic tissue water mobility. Modified fat-suppressed T2W sequences are adapted by adding sets of magnetisation gradients that, depending on their timing and magnitude (denoted as the b value, in seconds per square millimetre), induce sensitisation to tissue water diffusion in the resulting images. The water diffusivity can be calculated (apparent diffusion coefficient [ADC] value, in square micrometres per second)  and reflects the freedom of water movement. At the cellular level, water mobility is determined by tissue architectural properties such as cellular density, cellular arrangements, vascularity and extracellular space, tissue viscosity, and tortuosity. A negative correlation between cellular density and ADC value is usually found in soft tissue tumours . Similarity, negative correlations between PCa tumour proliferation and ADC values have been recorded  and .
Two kinds of images are produced from diffusion sequences: a set of qualitative DW images (one for each b value) and one quantitative ADC map, both of which need to be assessed. High–b value images are often reconstructed (using maximum-intensity projections) to appear “PET-like,” wherein the distribution of malignant disease appears bright (or dark on inverted grey-scale images) (Fig 1, Fig 3, Fig 4, and Fig 5; Supplementary Figs. 2–4). On whole-body DW imaging (WB-DWI), infiltrative skeletal metastases appear as focal or diffuse areas of high signal intensity on high–b value images on a background of the lower signal intensity of the normal bone marrow , , and .
Monitoring therapy response to docetaxel chemotherapy. Clinical details: A man aged 76 yr with metastatic castrate-resistant prostate cancer treated with docetaxel chemotherapy. Examinations were obtained at baseline (prostate-specific antigen [PSA] 427 ng/ml) and after three cycles (PSA 301 ng/ml) and six cycles (PSA 136 ng/ml). Clinical question: extent of tumour response. Whole-body magnetic resonance imaging (MRI) scans were performed using a 1.5-T scanner. (a) Diffusion-weighted MRI with a b value of 900 s/mm2 (b900) and maximum-intensity projection (inverted grey scale, anterior projections) at the three time points (TPs; baseline [TP1] and after three [TP2] and six [TP3] cycles of docetaxel). Extensive bone disease was detected as decreasing in extent and intensity over the three TPs; residual bone disease can still be seen at TP3. Note the emergence of liver metastases (arrows) at TP2 that remain at TP3. (b) T2-weighted fat-saturation (T2W-FS) and T1-weighted (T1W) MRI at the three TPs. Very little change was observed in the T2W-FS images, but increased bone fat can be seen in the lower thoracic and lumbar spine on T1W images at TP3 (arrows); this is consistent with some response to treatment. (c) Segmented whole-body b900 MRI images at the three TPs, using signal normalisation across TPs and identical signal intensity thresholds. Corresponding apparent diffusion coefficient (ADC) histograms for the three TPs, in each case compared with TP1. The x-axis is the ADC value (in micrometres per second), and the y-axis is the relative frequency. TP1 (blue): 1142 ml of tumour is segmented. The histogram is unimodal with high kurtosis (mean ADC 712 μm2/s, kurtosis 10.1). TP2 (orange): 500 ml of tumour is segmented. The histogram is still unimodal but moves to the right and decreases kurtosis (mean ADC 1107 μm2/s, kurtosis 4.1). This finding is in keeping with therapy response. TP3 (green): 360 ml of tumour is segmented. The histogram is now bimodal with the left peak corresponding in value to TP1, and the right peak remains at the value seen at TP2. The failure in the histogram to move further to the right at TP3, together with findings on the other images (liver metastases, persistent abnormalities on morphologic sequences), indicates nonresponse to treatment (secondary resistance). Docetaxel treatment was terminated, and enzalutamide treatment commenced. Image analysis was performed using prototype software (syngo.via Frontier MR Total Tumor Load; Siemens Healthcare, Erlangen, Germany).
TW1 = T1 weighted; T2W-FS = T2-weighted fat saturation; TP = time point.
Monitoring soft tissue disease therapy response. Clinical details: A man aged 68 yr with metastatic castrate-resistant prostate cancer after docetaxel and abiraterone, treated with mitoxantrone and prednisone. Examinations were obtained at baseline (prostate-specific antigen [PSA] 259 ng/ml) and after 12 wk of treatment (PSA 6093 ng/ml). Clinical question: query evidence of tumour response. whole-body magnetic resonance imaging scans were performed using a 1.5-T scanner. (Left panels) Diffusion-weighted images with a b value of 900 s/mm2 (b900) and inverted maximum-intensity projection (anterior projections). (Right panels) Planar bone scans (anterior view) at the corresponding time points. Extensive liver disease (horizontal white arrows) is visible, increasing in extent over 12 wk, indicating disease progression. There is lymph nodal disease progression (black arrowheads) within the abdomen and pelvis, including new nodal disease in the left supraclavicular fossa. There was no change in the bone deposits on the diffusion or bone scans (black arrows). Note increased lower limb lymph oedema visible on both scan types. Further active treatment was terminated.
It is important to emphasise that metastasis depiction by WB-DWI should always be correlated with appearances on complementary anatomic sequences to avoid false results  and . Correlations of signal intensity on high–b value images with ADC measurements is especially important for bone lesion characterisation. ADC values of normal marrow are lower than those of metastases due to the presence of marrow fat, with a cut-off value between 600 and 700 μm2/s , , and  when b values between 50 and 900 s/mm2 are used. Recommended cut-off values between normal marrow and tumour are set out in detail in the MET-RADS-P standards document .
Recently, Perez-Lopez et al. described a semiautomated segmentation tool to derive tumour volume estimates from high–b value images and to obtain global tumour ADC histograms. Tumour volume measurements from WB-DWI undertaken in this way have been shown to be prognostic in APC . Whole-body tumour volumes and ADC histograms can also be used to assess disease response to therapy , as illustrated in Fig. 4 and Supplementary Figure 2 and 4. The process of tumour cell lysis and apoptosis disrupts cellular membranes, increasing tissue water diffusivity and thus reducing the signal intensity on high–b value images and increasing ADC values , , and .
3. Evidence synthesis
3.1. Metastasis detection
Several meta-analyses have shown that the performance of WB-MRI for bone and soft tissue disease detection is comparable to that of FDG-PET/CT, both being significantly more accurate than BS and CT in majority of solid cancers on per-patient and per-lesion bases , , , and . Yang et al showed that for all metastatic disease detection on a per-patient basis, the pooled sensitivity estimates for FDG-PET/CT, CT, WB-MRI, and BS were 89.7%, 72.9%, 90.6%, and 86.0%, respectively. The pooled specificity estimates for FDG-PET/CT, CT, WB-MRI, and BS were 96.8%, 94.8%, 95.4%, and 81.4%, respectively .
The improved test performance of WB-MRI applies to skeletal assessments in APC specifically when CH-PET/CT is used as the comparator technique. Shen et al conducted a meta-analysis of 27 studies in APC and showed that MRI was superior to CH-PET/CT and BS for metastasis detection on a per-patient basis. On a per-patient basis, the pooled sensitivities for bone disease using CH-PET/CT, WB-MRI, and BS were 91% [95% confidence interval [CI], 83–96], 97% (95% CI, 91–99), 79% (95% CI, 73–83), respectively. The pooled specificities for bone metastasis detection using CH-PET/CT, WB-MRI, and BS were 99% (95% CI, 93–100), 95% (95% CI, 90–97), and 82% (95% CI, 78–85), respectively. . In a per-lesion analysis, CH-PET/CT had a higher diagnostic odds ratio that exceeded both BS and bone SPECT for detecting bone metastases.
A recent meta-analysis underscored the usefulness of DWI as a method that improves the detection of bone metastases. Liu et al.  evaluated 32 studies with 1507 patients and showed pooled sensitivity, specificity, and area under the curve for DWI of 95% (95% CI, 90–97), 92% (95% CI, 88–95), and 0.98, respectively, on a per-patient basis and 91% (95% CI, 87–94), 94% (95% CI, 90–96), and 0.97, respectively, on a per-lesion basis.
When evaluating the results of the above meta-analyses and, indeed, in all studies reporting test performance, readers should note that intrinsic verification biases are particularly prevalent at lesion-level analyses because it is simply not possible to obtain histopathology for every bone lesion detected, for ethical and practical clinical reasons  and . Consequently, most studies use combinations of imaging methods and/or follow-up as the standards of reference. Furthermore, as with all external imaging methods, microscopic metastasis depiction cannot be comprehensively undertaken.
3.2. Response assessment
Both preclinical and small-scale clinical studies indicate that DWI can be useful for the assessment of therapy response in malignant bone marrow disease in PCa. Preclinical mouse model studies of osseous PCa have shown increases in ADC values with therapeutic success. A mouse model of PCa bone metastases, for example, demonstrated increased ADC values in response to chemotherapy . ADC increases were also noted in PCa bone metastases models treated with combination docetaxel and anti-CCL2 therapy  and with cabozantinib .
Few systematic studies have been done in PCa patients with bone disease in response assessment settings  and ; there are many case series in the context of methodology development  and  and assessments of bone disease response when involvement occurs by other malignancies. The study of Reischauer et al, for example, found that mean ADC values of lesions increased significantly after hormonal therapy, in keeping with successful responses gauged by PSA declines . Slight ADC elevations were also noted in nonresponders, but these increases were <20%, whereas ADC increases in responders were of greater magnitude. Interestingly, there was also noticeable spatial heterogeneity within individual metastases, with the centre of the lesions having greater increases in ADC values, and variations between metastases in individual patients. Similar findings of increased ADC values in bone disease have been described for multiple myeloma, myeloproliferative diseases, breast cancers, and primary bone tumours with a variety of treatments, indicating that bone tumour ADC increases with successful treatment is a generic finding , , , , , , , , , and . This matches similar observations made in other organ systems .
Our review indicates that both WB-MRI and CH-PET/CT are suitable for wide deployment in disease detection settings, given their test performance, potential wide availability, and multiorgan evaluation capabilities. Sufficient data now indicate that WB-MRI has better accuracy for detecting bone metastases than BS to confidently recommend use for bone metastasis detection. Although further data, including comparative multimodal studies, are awaited in treatment-response assessment settings, a recent European Organisation for Research and Treatment of Cancer position paper also concluded that MRI offers a good “one size fits all” solution for patients who do not have substantial nonbone disease to assess therapy effectiveness .
The St. Gallen APCCC panellists correctly asked whether earlier detection of metastatic disease using highly sensitive imaging methods like WB-MRI and PET/CT will have significant clinical benefits in terms of significant impacts on QoL and OS . Similarly, they asked whether earlier detection of treatment failure or primary resistance by more sensitive methods, and subsequent modifications in life prolonging treatments, would have benefits in terms of maintaining QoL and improving OS. These questions are worth investigating because there are indications that earlier, timely detection and treatment initiation in oligometastatic APC may be beneficial . Some approved treatments are more suited to lower volume disease (local treatments such as surgery and targeted radiation, treatments targeting the androgen axis, and systemic immunotherapy). Furthermore, some treatments may work better when used in asymptomatic or minimally symptomatic patients with better performance status , , , and . Emerging guidelines are beginning to recommend prospective screening for metastatic disease in asymptomatic PCa patients, with a view to earlier initiation of treatments and clinical trial entry in oligometastatic disease, and in the setting of nonmetastatic CRPC , , and . To date, however, there are few data on the benefits of treatment modifications based on the earlier detection of treatment failure or primary resistance and on the negative QoL effects of continued treatments with ineffective drugs .
The cost of WB-MRI and PET/CT are often highlighted as a hindrance for clinical adoption in some health systems. However, costs are dependent on the availability of these technologies. Generally, within Europe, the cost of WB-MRI is comparable to the combined costs of CT and BS for the detection of bone and nodal metastases (Table 1)  and . Furthermore, because WB-MRI costs are largely determined by in-room table time, which is rapidly decreasing as MRI machine performance improves, we can expect to see WB-MRI scan times decrease.
There is a recognised need for standardisation of acquisition, interpretation, and reporting of WB-MRI . The MET-RADS-P imaging recommendations have been developed to address these needs . The WB-MRI methods proposed can be adapted for use in advanced metastatic breast cancer (MET-RADS-B) and for multiple myeloma (MET-RADS-MM); in passing, readers should note that WB-MRI is already recommended as the first-line tool for investigation in myeloma . The proposed MET-RADS-P system is suitable for clinical practice and can be incorporated into clinical trials, generating measures that can serve as new biomarkers, which in turn will require independent validation .
Initially, we suggest that WB-MRI be evaluated in clinical trials that assess the effects of treatments that are anticipated or known to kill tumour cells, such as those targeting the androgen axis, cytotoxic chemotherapy, and radium 223. More novel trials could include targeted radiotherapy for oligometastases, PARP inhibitors, and immunotherapies. In these studies, WB-MRI should be compared with current criteria (eg, changes in PSA, other biochemical markers, circulating tumour cells) and correlated to QoL measures, rates of skeletal events, and progression-free survival, so as to justify the inclusion of WB-MRI in future studies. Comparative clinical studies of test performance against established and emerging PET radiotracers would also be of interest. The latter are prerequisites for the successful introduction of WB-MRI into longer term follow-up studies that prospectively collect appropriate metadata that would allow objective assessments of whether WB-MRI is effective in directing patient care and supporting drug development.
Imaging techniques including WB-MRI and PET/CT scans have the potential to address the unmet need for robust imaging methods that allow tumour detection and therapy evaluations in APC. WB-MRI can detect bone metastases with higher sensitivity than BSs and with performance at least comparable to that of CH-PET/CT. Early and more accurate detection of tumour burden may have positive therapy implications. Importantly, WB-MRI provides clearer categorisation of bone metastasis response, unlike BSs, which only identify disease progression; more accurate assessments of therapy response (including heterogeneity of response) could further aid the rational development of targeted therapies.
There is a clear need for standardisation of WB-MRI and PET/CT technologies. The proposed MET-RADS-P system  enables complete characterisation of APC state using WB-MRI not only at the start of treatments but also over time as the disease evolves. MET-RADS-P allows the categorisation of patients with specific patterns of disease for clinical trial stratification. MET-RADS-P also enables the evaluation of the benefits of continuing therapy when there are signs that the disease is progressing (discordant responses). Clearly, WB-MRI is not at the point where it can support regulatory approvals of new therapeutic approaches. It is anticipated that as evidence accrues from clinical trials, more specific recommendations and/or algorithms incorporating WB-MRI and PET/CT will emerge. We recommend that WB-MRI and the MET-RADS-P system now be evaluated in clinical trials to assess the impact on the clinical management of APC.
Author contributions: Anwar R. Padhani had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Padhani, Lecouvet, Tunariu, Koh, De Keyzer, Collins, Sala, Schlemmer, Petralia, Vargas, Fanti, Tombal, de Bono.
Acquisition of data: Padhani, Lecouvet, Tunariu, Koh, De Keyzer, Collins.
Analysis and interpretation of data: Padhani, Lecouvet, Tunariu, Koh, De Keyzer, Collins, Sala, Schlemmer, Petralia, Vargas, Fanti, Tombal, de Bono.
Drafting of the manuscript: Padhani, Lecouvet, Tunariu, Koh, De Keyzer, Collins, Vargas, Fanti.
Critical revision of the manuscript for important intellectual content: Schlemmer, Petralia, Tombal, de Bono.
Statistical analysis: Padhani, Lecouvet.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Tombal, de Bono.
Other (specify): None.
Financial disclosures: Anwar R. Padhani certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Anwar R Padhani, Dow-Mu Koh, and David J. Collins have research agreements and speakers bureau declarations for Siemens Healthcare, an imaging company.
Funding/Support and role of the sponsor: We are grateful to the following funding agencies for funding our work: FRS-FNRS Televie, Fondation Contre le Cancer, Fondation Saint Luc (Belgium), and Memorial Sloane Kettering Cancer Center (Support Grant/Core Grant P30 CA008748). We also acknowledge support from Prostate Cancer UK and Movember to the London Movember Prostate Cancer Centre of Excellence at the Institute of Cancer Research and Royal Marsden and through an Experimental Cancer Medical Centre (ECMC) grant from Cancer Research UK and the Department of Health (Ref: C51/A7401). The authors acknowledge UK National Health Service funding to the National Institute for Health Research Biomedical Research Centre at the Royal Marsden and the Institute of Cancer Research. The funders played no role in the decision to undertake this review, the preparation of the manuscript, or the decision to submit the paper for publication.
Acknowledgments: We thank Aurelius Omlin and Silke Gillessen for their helpful clinical insights.
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a Paul Strickland Scanner Centre, Mount Vernon Hospital, Middlesex, UK
b Department of Radiology, Centre du Cancer and Institut de Recherche Expérimentale et Clinique, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
c Cancer Research UK Cancer Imaging Centre, Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Surrey, UK
d Department of Radiology, Medical Imaging Research Centre, University Hospitals Leuven, Leuven, Belgium
e Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
f Service of Nuclear Medicine, S.Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
g Department of Radiology, European Institute of Oncology, Milan, Italy
h Department of Radiology, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
i Department of Urology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
j Drug Development Unit, Institute of Cancer Research and the Royal Marsden NHS Trust, Surrey, UK
⁎ Corresponding author. Paul Strickland Scanner Centre, Mount Vernon Hospital, Rickmansworth Road, Northwood, Middlesex HA6 2RN, UK. Tel.: +44 0 1923 844751; fax: +44 0 1923 844600.
© 2016 European Association of Urology, Published by Elsevier B.V.