Clinical StudyValue of Fused 18F-Choline-PETMRI to Evaluate ProstateCancer Relapse in Patients Showing Biochemical Recurrenceafter EBRT Preliminary Results
Arnoldo Piccardo1 Francesco Paparo2 Riccardo Picazzo2 Mehrdad Naseri1
Paolo Ricci3 Andrea Marziano2 Lorenzo Bacigalupo2 Ennio Biscaldi2
Gian Andrea Rollandi2 Filippo Grillo-Ruggieri3 and Mohsen Farsad4
1 Nuclear Medicine Department EO Galliera Hospital Mura delle Cappuccine 14 16128 Genoa Italy2 Radiology Department EO Galliera Hospital Mura delle Cappuccine 14 16128 Genoa Italy3 Radiotherapy Department EO Galliera Hospital Mura delle Cappuccine 14 16128 Genoa Italy4Nuclear Medicine Department Azienda Sanitaria dellrsquoAlto Adige Via Lorenz Bohler 5 39100 Bolzano Italy
Correspondence should be addressed to Arnoldo Piccardo arnoldopiccardogallierait
Received 12 February 2014 Accepted 10 April 2014 Published 30 April 2014
Academic Editor Riccardo Schiavina
Copyright copy 2014 Arnoldo Piccardo et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited
Purpose We compared the accuracy of 18F-Choline-PETMRI with that of multiparametric MRI (mMRI) 18F-Choline-PETCT18F-Fluoride-PETCT and contrast-enhanced CT (CeCT) in detecting relapse in patients with suspected relapse of prostatecancer (PC) after external beam radiotherapy (EBRT) We assessed the association between standard uptake value (SUV) andapparent diffusion coefficient (ADC)Methods We evaluated 21 patients with biochemical relapse after EBRT Patients underwent18F-Choline-PETcontrast-enhanced (Ce)CT 18F-Fluoride-PETCT and mMRI Imaging coregistration of PET and mMRI wasperformed Results 18F-Choline-PETMRI was positive in 1821 patients with a detection rate (DR) of 86 DRs of 18F-Choline-PETCT CeCT and mMRI were 76 43 and 81 respectively In terms of DR the only significant difference was between 18F-Choline-PETMRI and CeCT On lesion-based analysis the accuracy of 18F-Choline-PETMRI 18F-Choline-PETCT CeCT andmMRIwas 99 95 70 and 85 respectively Accuracy sensitivity andNPVof 18F-Choline-PETMRIwere significantly higherthan those of bothmMRI andCeCTOnwhole-body assessment of bonemetastases the sensitivity of 18F-Choline-PETCT and 18F-Fluoride-PETCTwas significantly higher than that of CeCT Regarding local and lymphnode relapse we found a significant inversecorrelation between ADC and SUV-max Conclusion 18F-Choline-PETMRI is a promising technique in detecting PC relapse
1 Introduction
In patients affected by prostate cancer (PC) and treated withexternal beam radiation therapy (EBRT) relapsemay occur inabout 50 of cases within 5 years after treatment [1] and therecurrence rate of PC in these patients is reasonably higherthan in those treated with surgery Increasing levels of PSAafter EBRTare often related to PC recurrence especiallywhenPSA rises above 2 ngmL [2] and PSA doubling time is lt6months [3]
Several imaging techniques have been used to detect sitesof PC recurrence such as bone scintigraphy (BS) contrast-enhanced computed tomography (CeCT) and ultrasound(US) CeCT and US do not provide high diagnostic accuracyin detecting relapse [4 5] BS which has low specificityoften requires further adequate investigation In this field18F-Fluoride-PETCT may be helpful especially in highrisk PC patients as its high sensitivity and specificity indetecting bone lesions overcome the intrinsic limitations of
Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 103718 9 pageshttpdxdoiorg1011552014103718
2 BioMed Research International
Table 1 Characteristics of patients
Mean plusmn SD 95 CI for the mean Median 95 for the medianAge (years) 772 plusmn 51 748 to 79 78 (70ndash85) 35 to 77Mean serum PSA (ngmL) on inclusion 58 plusmn 34 543 to 74 49 (22ndash134) 731 to 80Gleason sum 81 plusmn 085 77 to 85 8 (7ndash9) 7 to 8Time interval EBRT-inclusion 239 plusmn 134 178 to 301 24 (6ndash68) 171 to 28
BS [6] At present the most promising tools are multipara-metricMRI (mMRI) andPETCTwith radio-labelled cholinederivatives MRI can accurately detect residual prostate can-cer and locoregional recurrence after EBRT [7] Choline-PETCT being a whole-body imaging technique may locatelymph nodes and bone metastases in the majority of patientstreated with EBRT [8ndash10] The simultaneous acquisition ofPET andmMRI with new PETMRI scanners may be helpfulespecially in doubtful cases [11] but this integrated imagingmodality is currently not easily available To date howeverlittle can be said about the accuracy of combined 18F-Choline-PETMRI in PC [12] and few studies have comparedthe accuracy of mMRI and 18F-Choline-PETCT in patientsaffected by recurrent PC [13]
The aim of this study was firstly to assess the diagnosticperformance of fused 18F-Choline-PETMRI in patients withsuspected relapse of PC after EBRT We also comparedthe accuracy of 18F-Choline-PETMRI with that of mMRI18F-Choline-PETCT 18F-Fluoride-PETCT and CeCT indetecting local recurrence lymph node and bonemetastasesWe finally assessed the association between the standarduptake value (SUV-max) of PET and apparent diffusioncoefficient (ADC) value of local recurrence and lymph nodemetastases
2 Materials and Methods
21 Patient Population We prospectively evaluated 21 PCpatients who showed biochemical relapse after first-linetreatment with EBRT Sixteen patients were treated only withEBRT and the others were treated with EBRT and androgendeprivation therapy (ADT) We included in our study onlypatients with Gleason score ge7 PSA ge 2 ngmL and PSAdoubling time (DT) le6 months All patients underwentintegrated 18F-Choline-PETcontrast-enhanced (Ce)CT 18F-Fluoride-PETCT and mMRI within ten days The maincharacteristics of the patients are summarized in Table 1 TheLocal Ethics Committee approved the study All patients hadbeen treated exclusively with EBRT as primary treatmentPatients had received a dose range of 74ndash81Gy to the prostategland and 72ndash74Gy to the prostatic fossa Therapy wasperformed in accordance with EAU guidelines [14] Allpatients at the time of EBRT were classified as N0
22 18F-Choline-PETCeCT Protocol 18F-Choline-PETCTwas performed in the fasting state (at least 6 h) An18F-Choline activity of 3MBqkg (IASOCholine IASONLabormedizinGesmbhampCoKg LinzAustria)was adminis-tered intravenously data were acquired 101015840 after the injection
by means of a dedicated PETCT system (Discovery STGeneral Electric Healthcare Technologies Milwaukee WI)Low dose CT was acquired for both attenuation correctionand topographic localization The CT parameters used foracquisition were 140 kV 80mA and 05 s per rotation andpitch 6 1 with a slice thickness of 325mm equal to that ofPET PET was acquired in 3D mode from the upper neck tothe upper thighs by means of sequential fields of view eachcovering 12 cm (matrix of 256times 256) over an acquisition timeof 3min Finally a whole-body CeCT (120 kVp 119911-axis tubecurrentmodulationwithminimummaximummA 200600)was acquired during the portal venous phase 50 s afterreaching the threshold of 100UH in the mid thoracic aortausing a bolus tracking technique Iopromide 370mg ImL(Ultravist BayerHealthCare Pharmaceuticals IncMontvilleNJ) was used as intravenous iodinated contrast mediumin all patients and it was administered at a fixed flowrate of 3mLs to guarantee a constant iodine delivery rateof 12 g Is 18F-Choline-PETCT CeCT and 18F-Choline-PETCeCT studies were visualized on Xeleris Workstationversion 21753 (General ElectricMilwaukeeWIUSA)whichallowed PETCT and PETCeCT fusion and CeCT multipla-nar reconstructions
23 18F-Fluoride-PETCT Protocol PET acquisition started60min after intravenous injection of 370MBq 18F-labelledNa F (IASOflu-IASON GmbHGraz Austria) and included10ndash12 bed positions All PET scans were acquired in 3Dmode(3min emissions per bed position) and were reconstructedby using an iterative reconstruction algorithm CT acquisi-tion data were optimized to obtain diagnostic CT imagesalso with small image reconstruction thickness using thefollowing data 120 kV 120ndash400mAwith an automatic systemof dose optimisation (Auto-mA General Electric MedicalSystems) tube rotation time 05 s 16mm times 125mm detectorconfiguration and table feed 1375mm per rotation Overallwe acquired only one CT scan obtaining two image recon-struction thicknesses 375mm (for attenuation correctionand anatomic localization) and 125mm (for multiplanarreconstruction) No iodinated contrast mediumwas injectedCT acquisition was performed from the skull vertex to thedistal femur with the same field of view used for 18F-Fluoride-PET
24 Multiparametric MRI Multiparametric MRI (mMRI)was performed with a 15T MRI scanner (Signa HDxt GEHealthcare Milwaukee WI) equipped with 8-channel pelvicphased-array coil according to a standardized protocolFSE T2-weighted (T2w) sequences (slice thickness 4mm
BioMed Research International 3
interslice gap 04mm in plane resolution 06 times 06mm) witha large field of viewwere first oriented in the three orthogonalplanes (sagittal axial and coronal) without fat saturationenabling identification of the prostate gland and pelvic lymphnode stations High-resolution oblique axial and coronalscans (slice thickness 3ndash35mm interslice gap 03mm) werefurther oriented perpendicular and parallel to the rectopro-static plane in order to avoid misinterpretation due to partialvolume effects Diffusion-weighted imaging (DWI) sequence(b 1000 sm2 TR 3400 TE 763 bandwidth 250 kHz FOV 40times 40 slice thickness 40mm interslice gap 04mm matrix128 times 128 number of excitations 6 and in plane resolution 15times 15mm) was acquired in the axial plane using same slicelocations of the first FSE T2w sequence Dynamic contrast-enhancedMRI (DCE-MRI) was acquired during intravenousinjection of the paramagnetic contrast medium with a flowrate of 3mLs A 3-dimensional spoiled gradient echo fatsaturated T1-weighted (LAVA) pulse sequence was repeatedin the axial plane 27 times with a temporal resolution of12 s during the injection of a single dose of contrast agentAn axial STIR sequence (TR 5000ms TE 801ms inversiontime 150ms thickness 5mm interslice gap 05mm matrix256 times 256) was performed to detect focal bone lesions andfor comparingmMRIwith PET techniques (ie 18F-Choline-PETCT and 18F-NaF PETCT) in the detection of bonerecurrence Antiperistaltic drugs were given for minimizingmotion artifacts due to intestinal peristalsis at the beginningof each mMRI examination
25 Fused 18F-Choline-PETMRI Multimodal imagingcoregistration fusion and synchronized navigation wereperformed using a novel dedicated software developed forresearch purposes (Quanta Prostate Camelot BiomedicalSystems srl Genoa Italy) This software was developedfor aiding multiparametric MRI (mMRI) interpretation andreporting as well as multimodal MRIPET coregistrationQuanta Prostate is able to simultaneously display differentMRI datasets allowing calculation of color-coded ADCmaps from DWI sequences and wash-inwash-out rate mapsfrom time-intensity curves of DCE-MRI Color-coded ADCand perfusion maps can be overlapped on T2w images andexamined with different levels of transparency Using QuantaProstate a deformable registration technique (employingnonlinear transformation and spatially varying deformablemodels) is applied for MRIPET coregistration in order tocompensate for changes in patient positioning and localdeformations between different imaging datasets (eg dueto varying degrees of filling of the urinary bladder) OnceMRIPET coregistration is performed the operator canperform quantitative measurements (ADC and SUV-maxvalues) by drawing a ROI on the currently selected ADC orSUV map
3 Image Interpretation
31 18F-Choline-PETCT and 18F-Fluoride-PETCT 18F-Choline-PETCT and 18F-Fluoride-PETCT studies were in-terpreted visually and semiquantitatively using themaximum
standardized uptake value (SUV-max) on a patient-by-patient and lesion-by-lesion basis using the above mentioneddedicated software to review fused PETCT imagesHowever no SUV-max cut-off value have been introducedand SUV was calculated for each lesion just to support visualinterpretation
On 18F-Choline-PETCT any focal and nonphysiologicaluptake corresponding to prostate parenchyma abdominaland pelvic lymph nodes and bone was considered as patho-logical
On 18F-Fluoride-PETCT bone lesions were consideredto be malignant if a high and focal 18F-Fluoride uptake wasdetected without any morphological changes on CT or ahigh and focal 18F-Fluoride uptake was associated to typicalmorphological changes on CT
32 Multiparametric MRI All mMRI were reviewed on adedicated workstation on (Advantage Workstation 46 Gen-eral Electric Medical Systems) using a tool for mMRI visual-ization and reporting A definitive diagnosis of cancer recur-rence (ie local lymph nodal and skeletal recurrence) wasformulated after examining eachMRI examination reportingthe number of lymph nodal and skeletal lesions Findingsindicative of local recurrence were identified accordingto ESUR prostate MR guidelines 2012 considering thatradiation-induced fibrosis and shrinkage of the gland mayoften hinder lesion detection [15] DWI sequence was exam-ined by generating anADCmap searching for intraglandularnodular foci characterized by restriction of water diffusionrelative to the surrounding prostate parenchyma ADC valueof the glandular area affected by recurrent disease was regis-tered and compared with the corresponding SUV-max valueof 18F-Choline-PETCT On DCE-MRI sequences prostatecancer recurrence was recognized as an early enhancing areain contrast to the surrounding glandular tissue A quantitativewash-in perfusionmapwas generated for aiding the detectionof hypervascularized foci within the prostate gland Thefollowing morphological and size criteria were used to definea metastatic lymph node short axis diameter gt10mm for anoval lymph node and diameter gt8mm for a round lymphnode The ADC value of the most PET-positive lymph nodeof each lymph nodal station involved by recurrent diseasewas registered and compared to the SUV-max value of 18F-Choline-PETCT Axial STIR sequence was employed tosearch bone metastases that appear as hyperintense focallesions within the spongy or cortical bone compartments
33 Contrast-Enhanced CT On CT scans the separationbetween the prostate and the levator ani muscle is poorlydefined and intraprostatic anatomy is not well demonstratedOnly the following morphologic criteria were applied fordefining local recurrence prostate enlargement with focalcapsule bulging nodular areas of inhomogeneous contrastenhancement within the peripheral gland sign of extracap-sular extension Bone metastases were considered to havean osteosclerotic or mixed (ie osteolytic and osteosclerotic)appearance
4 BioMed Research International
Table 2 Patient-based analysis DR was calculated for each single diagnostic modality in each site of disease
34 Multimodal Fusion Imaging On 18F-Choline-PETMRIany focus of nonphysiological uptake corresponding to anysuspected mMRI finding in prostate gland was consideredsuggestive for local recurrence Any focal uptake correspond-ing to mMRI detectable abdominal and pelvic lymph nodeswas considered as lymph node metastasis Any focal 18F-Choline bone uptake corresponding or not to a pathologicalfinding on mMRI was considered as bone metastasis
35 Standard of Reference CeCT and mMRI at 12 monthsserved as the standard of reference for the final discrimina-tion between true positive true negative false positive andfalse negative results Further available follow-up informationwas provided by response to salvage therapy laboratoryteststumourmarkers US-guided transrectal prostate biopsyand other imaging studies (X-ray studies and bone scans)Patients and lesions were considered true negative if follow-up cross-sectional imaging studies and transrectal ultrasoundwere both negative and the patients had stable PSA valuesA median clinical and imaging follow-up time of 14 months(range 12ndash18) was available for each patient
Histopathologic confirmation was available in 3 out of 5patients showing only local recurrence and in one out of sixpatients affected by lymph node metastases
36 Statistical Analysis No specific sample size calculationwas performed given the pilot nature of the study Cate-gorical data were summarised as number (percentage) ofsubjectslesions continuous data were summarised as meanstandard deviation median and range The normal distribu-tion of datasets of different variables was assessed bymeans oftheDrsquoAgostino-Pearson testWhendatasets did not follow thenormal distribution nonparametric tests were used insteadof parametric ones The degree of correlation between ADCand -max values for local and lymph node recurrence wasassessed by the Spearman rank test The diagnostic perfor-mance of different diagnostic modalities (ie mMRI CeCT18F-Choline-PETCT and 18F-NaF PETCT) for determiningthe presence of recurrent disease was calculated using 2 times 2tables Sensitivity specificity positive and negative predictivevalues and overall diagnostic accuracy were calculatedThe diagnostic performances of different modalities werecompared by means of the Fisher exact test for proportionswith level of statistical significance set at 005
4 Results
41 Patient-Based Analysis Fused 18F-Choline-PETMRIwas positive in 18 of 21 patients with an overall detection rate(DR) of 86 Local relapse was detected in 6 patients oneof whom was also affected by bone metastases Lymph nodemetastases were detected in 6 patients two of whom also hadbone involvement Six patients showed only bonemetastasesThe DR of 18F-Choline-PETCT CeCT and mMRI was 76(1621 patients) 43 (921 patients) and 81 (1721 patients)respectively The difference between the DR of multimodalfusion imaging 18F-Choline-PETMRI and that of CeCT wasstatistically significant (119875 = 0016) while comparing mMRIand 18F-Choline-PETCT with CeCT it only tended to besignificant (119875 = 0093 for bothmodalities) No significant dif-ference was found between 18F-Choline-PETMRI and 18F-Choline-PETCT nor between 18F-Choline-PETMRI andmMRI (119875 = 067 for both comparisons) Table 2 shows theDRs recorded when the different sites of PC recurrence wereconsidered separately Considering all skeletal metastasesincluding those beyond the field-of-view (FOV) of mMRIand multimodal fusion imaging 18F-Choline-PETMRI 18F-Fluoride-PETCT provided the highest DR (detecting all 9patients affected by bone metastases) which was found to besignificantly different from that of CeCT (119875 = 0034)
42 Lesion-Based Analysis Overall 133 lesions were detectedin our analysis 102 of which were found in the pelvis andlower abdominal quadrants Of these 79 were malignant(including local recurrences and lymph node and skeletalmetastases) and 54 were benign according to the standardof reference Specifically we detected 6 local recurrences 40pelvic lymph node metastases and 33 bone metastases Sixtyof these 79 lesions were found in the field-of-view (FOV) ofmMRI encompassing pelvis and lower abdominal quadrantsConsidering only the FOV of mMRI the overall accuracyof fused 18F-Choline-PETMRI 18F-Choline-PETCT CeCTand mMRI was 99 95 70 and 85 respectivelySensitivity specificity PPV and NPV of different diagnosticmodalities were as follows 100 98 98 and 100 forfused 18F-Choline-PETMRI 95 98 98 and 93 for18F-Choline-PETCT 50 100 100 and 58 for CeCT75 95 96 and 75 for mMRI
The accuracy sensitivity and NPV of fused 18F-Choline-PETMRI were significantly higher than those of bothmMRI(119875 lt 005) and CeCT (119875 lt 005) No differences in
BioMed Research International 5
Table 3 Lesion-based analysis and sensitivity in lesion detection according to different sites of recurrencemetastases (ie local recurrencelymph nodes and bone) obtained by mMRI 18F-Choline PETMRI CeCT and 18F-Choline PETCT
terms of specificity (119875 gt 005) and PPV (119875 gt 005)were observed between the different diagnostic modalitiesA lesion-based analysis to determine the sensitivity of eachmodality in detecting recurrent lesions according to differentanatomical locations (ie local recurrence lymph nodes andbone metastases) was also performed these results are sum-marized in Table 3 18F-Choline-PETMRI was more usefulin detecting local relapse identifying more local recurrences(66 100) than 18F-Choline-PETCT (46 67) Two casesof local recurrence are illustrated in Figures 1 and 2 Howeverthe statistical difference between these two modalities wasnot significant owing to the low number of local recurrences(119875 = 045) Fused 18F-Choline-PETMRI showed signifi-cantly higher sensitivity in locating lymph node metastasesthan mMRI (119875 = 00002) and CeCT (119875 lt 00001) Onecase is illustrated in Figure 3 On the other handmultimodal-ity fusion 18F-Choline-PETMRI and 18F-Choline-PETCTdetected the same number of lymph node metastases Withregard to whole-body assessment we compared 18F-Choline-PETCT CeCT and 18F-Fluoride-PETCT in terms of theirability to detect bonemetastases Two cases of skeletal metas-tases are illustrated in Figures 4 and 5 The data regardingsensitivity are summarized in Table 4
5 Correlation between ADC Valuesand SUV-max
With regard to local recurrences we found a high and sta-tistically significant inverse correlation between ADC value(74 times 10minus4 plusmn 2 times 10minus4mm2s median 92 times 10minus4 [74 times10minus4ndash132 times 10minus3]) and SUV-max (33 plusmn 13 median 39 [14ndash48]) (r = minus083 119875 = 004) With regard to lymph noderecurrences we found a moderate and statistically significantinverse correlation between ADC value (14 times 10minus3plusmn 11 times10minus3mm2s median 98 times 10minus3 [12 times 10minus4ndash41 times 10minus3]) andSUV-max (7 plusmn 41 median 64 [16ndash14]) (r = minus06 119875 = 002)
6 Discussion
In this pilot study we used different morphologicaland functional imaging modalities (ie mMRI CeCT18F-Choline-PETCT 18F-Fluoride-PETCT and fused18F-Choline-PETMRI) to prospectively examine a smallhomogeneous cohort of 21 PC patients with biochemicalrecurrence after first-line EBRT The clinical implementationof 18F-Choline-PETCT and mMRI in assessing recurrentPC after EBRT is currently yielding encouraging results
6 BioMed Research International
(a) (b) (c)
(d) (e) (f)
Figure 1 72-year-oldman with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense focalarea close to the midline (arrow) The ADCmap (b) demonstrates that the nodular area (arrow) has significantly lower ADC values than thesurrounding parenchyma The wash-in perfusion map (c) shows a high wash-in rate (arrow) On the 18F-Choline-PETCT axial image (d) adoubtful PET-positive focus (arrow) is appreciable while the lesion is not detectable on CeCT axial image (e) Fused 18F-Choline-PETMRIimage (f) demonstrates precise correspondence between PET-positive focus and MRI finding (arrow)
(a) (b)
(c) (d)
Figure 2 75-year-old man with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense area(arrow) in the posterior left lateral aspect of the prostate apex The ADC map (b) demonstrates that the hypointense nodular area has lowerADC values than the surrounding parenchyma (arrow) On 18F-Choline-PET axial scan (c) a well-defined PET-positive focus is appreciable(arrow) Fused 18F-Choline-PETMRI image (d) shows exact correspondence between PET-positive focus and MRI finding (arrow)
BioMed Research International 7
(a) (b) (c)
(d) (e)
Figure 3 78-year-old man with a bone metastasis in the right proximal femur The bone lesion (arrow) is well detectable on STIR (a) 18F-Fluoride-PETCT (b) and fused 18F-Choline-PETMRI axial images while it is not visible on T2-weighted (d) and CeCT (e) axial images
(a) (b) (c)
Figure 4 82-year-old man with a bone metastasis in the posterior arch of the left 10th rib The lesion (arrow) is not definitely appreciableon the CeCT axial image (a) and is not detectable on the 18F-Choline-PET axial scan (b) On the 18F-Fluoride-PETCT axial image (c) theskeletal metastasis is well detectable
[7 16] and this growing evidence is confirmed by the dataof our study showing high DRs for both modalities (ie 76and 81 resp) Multimodal fusion imaging between 18F-Choline-PETCT and mMRI (fused 18F-Choline-PETMRI)yielded an even better DR (ie 86) thus underscoringthat multimodal coregistration synchronized navigationand combined interpretation are more valuable than theindividual separate assessment of different diagnostic
techniques Only preliminary studies [11 12] are available onthe simultaneous acquisition of PET andMRIwith integratedPETMRI scanners on PC and to date only one paper hasaddressed the issue of multimodal fusion PETMRI imaging(with the two modalities acquired at separate times withdifferent scanners) in the assessment of 17 patients withprimary prostate cancer [17] To the best of our knowledgeour study was the first to investigate the diagnostic value of
8 BioMed Research International
(a) (b) (c)
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
Mean plusmn SD 95 CI for the mean Median 95 for the medianAge (years) 772 plusmn 51 748 to 79 78 (70ndash85) 35 to 77Mean serum PSA (ngmL) on inclusion 58 plusmn 34 543 to 74 49 (22ndash134) 731 to 80Gleason sum 81 plusmn 085 77 to 85 8 (7ndash9) 7 to 8Time interval EBRT-inclusion 239 plusmn 134 178 to 301 24 (6ndash68) 171 to 28
BS [6] At present the most promising tools are multipara-metricMRI (mMRI) andPETCTwith radio-labelled cholinederivatives MRI can accurately detect residual prostate can-cer and locoregional recurrence after EBRT [7] Choline-PETCT being a whole-body imaging technique may locatelymph nodes and bone metastases in the majority of patientstreated with EBRT [8ndash10] The simultaneous acquisition ofPET andmMRI with new PETMRI scanners may be helpfulespecially in doubtful cases [11] but this integrated imagingmodality is currently not easily available To date howeverlittle can be said about the accuracy of combined 18F-Choline-PETMRI in PC [12] and few studies have comparedthe accuracy of mMRI and 18F-Choline-PETCT in patientsaffected by recurrent PC [13]
The aim of this study was firstly to assess the diagnosticperformance of fused 18F-Choline-PETMRI in patients withsuspected relapse of PC after EBRT We also comparedthe accuracy of 18F-Choline-PETMRI with that of mMRI18F-Choline-PETCT 18F-Fluoride-PETCT and CeCT indetecting local recurrence lymph node and bonemetastasesWe finally assessed the association between the standarduptake value (SUV-max) of PET and apparent diffusioncoefficient (ADC) value of local recurrence and lymph nodemetastases
2 Materials and Methods
21 Patient Population We prospectively evaluated 21 PCpatients who showed biochemical relapse after first-linetreatment with EBRT Sixteen patients were treated only withEBRT and the others were treated with EBRT and androgendeprivation therapy (ADT) We included in our study onlypatients with Gleason score ge7 PSA ge 2 ngmL and PSAdoubling time (DT) le6 months All patients underwentintegrated 18F-Choline-PETcontrast-enhanced (Ce)CT 18F-Fluoride-PETCT and mMRI within ten days The maincharacteristics of the patients are summarized in Table 1 TheLocal Ethics Committee approved the study All patients hadbeen treated exclusively with EBRT as primary treatmentPatients had received a dose range of 74ndash81Gy to the prostategland and 72ndash74Gy to the prostatic fossa Therapy wasperformed in accordance with EAU guidelines [14] Allpatients at the time of EBRT were classified as N0
22 18F-Choline-PETCeCT Protocol 18F-Choline-PETCTwas performed in the fasting state (at least 6 h) An18F-Choline activity of 3MBqkg (IASOCholine IASONLabormedizinGesmbhampCoKg LinzAustria)was adminis-tered intravenously data were acquired 101015840 after the injection
by means of a dedicated PETCT system (Discovery STGeneral Electric Healthcare Technologies Milwaukee WI)Low dose CT was acquired for both attenuation correctionand topographic localization The CT parameters used foracquisition were 140 kV 80mA and 05 s per rotation andpitch 6 1 with a slice thickness of 325mm equal to that ofPET PET was acquired in 3D mode from the upper neck tothe upper thighs by means of sequential fields of view eachcovering 12 cm (matrix of 256times 256) over an acquisition timeof 3min Finally a whole-body CeCT (120 kVp 119911-axis tubecurrentmodulationwithminimummaximummA 200600)was acquired during the portal venous phase 50 s afterreaching the threshold of 100UH in the mid thoracic aortausing a bolus tracking technique Iopromide 370mg ImL(Ultravist BayerHealthCare Pharmaceuticals IncMontvilleNJ) was used as intravenous iodinated contrast mediumin all patients and it was administered at a fixed flowrate of 3mLs to guarantee a constant iodine delivery rateof 12 g Is 18F-Choline-PETCT CeCT and 18F-Choline-PETCeCT studies were visualized on Xeleris Workstationversion 21753 (General ElectricMilwaukeeWIUSA)whichallowed PETCT and PETCeCT fusion and CeCT multipla-nar reconstructions
23 18F-Fluoride-PETCT Protocol PET acquisition started60min after intravenous injection of 370MBq 18F-labelledNa F (IASOflu-IASON GmbHGraz Austria) and included10ndash12 bed positions All PET scans were acquired in 3Dmode(3min emissions per bed position) and were reconstructedby using an iterative reconstruction algorithm CT acquisi-tion data were optimized to obtain diagnostic CT imagesalso with small image reconstruction thickness using thefollowing data 120 kV 120ndash400mAwith an automatic systemof dose optimisation (Auto-mA General Electric MedicalSystems) tube rotation time 05 s 16mm times 125mm detectorconfiguration and table feed 1375mm per rotation Overallwe acquired only one CT scan obtaining two image recon-struction thicknesses 375mm (for attenuation correctionand anatomic localization) and 125mm (for multiplanarreconstruction) No iodinated contrast mediumwas injectedCT acquisition was performed from the skull vertex to thedistal femur with the same field of view used for 18F-Fluoride-PET
24 Multiparametric MRI Multiparametric MRI (mMRI)was performed with a 15T MRI scanner (Signa HDxt GEHealthcare Milwaukee WI) equipped with 8-channel pelvicphased-array coil according to a standardized protocolFSE T2-weighted (T2w) sequences (slice thickness 4mm
BioMed Research International 3
interslice gap 04mm in plane resolution 06 times 06mm) witha large field of viewwere first oriented in the three orthogonalplanes (sagittal axial and coronal) without fat saturationenabling identification of the prostate gland and pelvic lymphnode stations High-resolution oblique axial and coronalscans (slice thickness 3ndash35mm interslice gap 03mm) werefurther oriented perpendicular and parallel to the rectopro-static plane in order to avoid misinterpretation due to partialvolume effects Diffusion-weighted imaging (DWI) sequence(b 1000 sm2 TR 3400 TE 763 bandwidth 250 kHz FOV 40times 40 slice thickness 40mm interslice gap 04mm matrix128 times 128 number of excitations 6 and in plane resolution 15times 15mm) was acquired in the axial plane using same slicelocations of the first FSE T2w sequence Dynamic contrast-enhancedMRI (DCE-MRI) was acquired during intravenousinjection of the paramagnetic contrast medium with a flowrate of 3mLs A 3-dimensional spoiled gradient echo fatsaturated T1-weighted (LAVA) pulse sequence was repeatedin the axial plane 27 times with a temporal resolution of12 s during the injection of a single dose of contrast agentAn axial STIR sequence (TR 5000ms TE 801ms inversiontime 150ms thickness 5mm interslice gap 05mm matrix256 times 256) was performed to detect focal bone lesions andfor comparingmMRIwith PET techniques (ie 18F-Choline-PETCT and 18F-NaF PETCT) in the detection of bonerecurrence Antiperistaltic drugs were given for minimizingmotion artifacts due to intestinal peristalsis at the beginningof each mMRI examination
25 Fused 18F-Choline-PETMRI Multimodal imagingcoregistration fusion and synchronized navigation wereperformed using a novel dedicated software developed forresearch purposes (Quanta Prostate Camelot BiomedicalSystems srl Genoa Italy) This software was developedfor aiding multiparametric MRI (mMRI) interpretation andreporting as well as multimodal MRIPET coregistrationQuanta Prostate is able to simultaneously display differentMRI datasets allowing calculation of color-coded ADCmaps from DWI sequences and wash-inwash-out rate mapsfrom time-intensity curves of DCE-MRI Color-coded ADCand perfusion maps can be overlapped on T2w images andexamined with different levels of transparency Using QuantaProstate a deformable registration technique (employingnonlinear transformation and spatially varying deformablemodels) is applied for MRIPET coregistration in order tocompensate for changes in patient positioning and localdeformations between different imaging datasets (eg dueto varying degrees of filling of the urinary bladder) OnceMRIPET coregistration is performed the operator canperform quantitative measurements (ADC and SUV-maxvalues) by drawing a ROI on the currently selected ADC orSUV map
3 Image Interpretation
31 18F-Choline-PETCT and 18F-Fluoride-PETCT 18F-Choline-PETCT and 18F-Fluoride-PETCT studies were in-terpreted visually and semiquantitatively using themaximum
standardized uptake value (SUV-max) on a patient-by-patient and lesion-by-lesion basis using the above mentioneddedicated software to review fused PETCT imagesHowever no SUV-max cut-off value have been introducedand SUV was calculated for each lesion just to support visualinterpretation
On 18F-Choline-PETCT any focal and nonphysiologicaluptake corresponding to prostate parenchyma abdominaland pelvic lymph nodes and bone was considered as patho-logical
On 18F-Fluoride-PETCT bone lesions were consideredto be malignant if a high and focal 18F-Fluoride uptake wasdetected without any morphological changes on CT or ahigh and focal 18F-Fluoride uptake was associated to typicalmorphological changes on CT
32 Multiparametric MRI All mMRI were reviewed on adedicated workstation on (Advantage Workstation 46 Gen-eral Electric Medical Systems) using a tool for mMRI visual-ization and reporting A definitive diagnosis of cancer recur-rence (ie local lymph nodal and skeletal recurrence) wasformulated after examining eachMRI examination reportingthe number of lymph nodal and skeletal lesions Findingsindicative of local recurrence were identified accordingto ESUR prostate MR guidelines 2012 considering thatradiation-induced fibrosis and shrinkage of the gland mayoften hinder lesion detection [15] DWI sequence was exam-ined by generating anADCmap searching for intraglandularnodular foci characterized by restriction of water diffusionrelative to the surrounding prostate parenchyma ADC valueof the glandular area affected by recurrent disease was regis-tered and compared with the corresponding SUV-max valueof 18F-Choline-PETCT On DCE-MRI sequences prostatecancer recurrence was recognized as an early enhancing areain contrast to the surrounding glandular tissue A quantitativewash-in perfusionmapwas generated for aiding the detectionof hypervascularized foci within the prostate gland Thefollowing morphological and size criteria were used to definea metastatic lymph node short axis diameter gt10mm for anoval lymph node and diameter gt8mm for a round lymphnode The ADC value of the most PET-positive lymph nodeof each lymph nodal station involved by recurrent diseasewas registered and compared to the SUV-max value of 18F-Choline-PETCT Axial STIR sequence was employed tosearch bone metastases that appear as hyperintense focallesions within the spongy or cortical bone compartments
33 Contrast-Enhanced CT On CT scans the separationbetween the prostate and the levator ani muscle is poorlydefined and intraprostatic anatomy is not well demonstratedOnly the following morphologic criteria were applied fordefining local recurrence prostate enlargement with focalcapsule bulging nodular areas of inhomogeneous contrastenhancement within the peripheral gland sign of extracap-sular extension Bone metastases were considered to havean osteosclerotic or mixed (ie osteolytic and osteosclerotic)appearance
4 BioMed Research International
Table 2 Patient-based analysis DR was calculated for each single diagnostic modality in each site of disease
34 Multimodal Fusion Imaging On 18F-Choline-PETMRIany focus of nonphysiological uptake corresponding to anysuspected mMRI finding in prostate gland was consideredsuggestive for local recurrence Any focal uptake correspond-ing to mMRI detectable abdominal and pelvic lymph nodeswas considered as lymph node metastasis Any focal 18F-Choline bone uptake corresponding or not to a pathologicalfinding on mMRI was considered as bone metastasis
35 Standard of Reference CeCT and mMRI at 12 monthsserved as the standard of reference for the final discrimina-tion between true positive true negative false positive andfalse negative results Further available follow-up informationwas provided by response to salvage therapy laboratoryteststumourmarkers US-guided transrectal prostate biopsyand other imaging studies (X-ray studies and bone scans)Patients and lesions were considered true negative if follow-up cross-sectional imaging studies and transrectal ultrasoundwere both negative and the patients had stable PSA valuesA median clinical and imaging follow-up time of 14 months(range 12ndash18) was available for each patient
Histopathologic confirmation was available in 3 out of 5patients showing only local recurrence and in one out of sixpatients affected by lymph node metastases
36 Statistical Analysis No specific sample size calculationwas performed given the pilot nature of the study Cate-gorical data were summarised as number (percentage) ofsubjectslesions continuous data were summarised as meanstandard deviation median and range The normal distribu-tion of datasets of different variables was assessed bymeans oftheDrsquoAgostino-Pearson testWhendatasets did not follow thenormal distribution nonparametric tests were used insteadof parametric ones The degree of correlation between ADCand -max values for local and lymph node recurrence wasassessed by the Spearman rank test The diagnostic perfor-mance of different diagnostic modalities (ie mMRI CeCT18F-Choline-PETCT and 18F-NaF PETCT) for determiningthe presence of recurrent disease was calculated using 2 times 2tables Sensitivity specificity positive and negative predictivevalues and overall diagnostic accuracy were calculatedThe diagnostic performances of different modalities werecompared by means of the Fisher exact test for proportionswith level of statistical significance set at 005
4 Results
41 Patient-Based Analysis Fused 18F-Choline-PETMRIwas positive in 18 of 21 patients with an overall detection rate(DR) of 86 Local relapse was detected in 6 patients oneof whom was also affected by bone metastases Lymph nodemetastases were detected in 6 patients two of whom also hadbone involvement Six patients showed only bonemetastasesThe DR of 18F-Choline-PETCT CeCT and mMRI was 76(1621 patients) 43 (921 patients) and 81 (1721 patients)respectively The difference between the DR of multimodalfusion imaging 18F-Choline-PETMRI and that of CeCT wasstatistically significant (119875 = 0016) while comparing mMRIand 18F-Choline-PETCT with CeCT it only tended to besignificant (119875 = 0093 for bothmodalities) No significant dif-ference was found between 18F-Choline-PETMRI and 18F-Choline-PETCT nor between 18F-Choline-PETMRI andmMRI (119875 = 067 for both comparisons) Table 2 shows theDRs recorded when the different sites of PC recurrence wereconsidered separately Considering all skeletal metastasesincluding those beyond the field-of-view (FOV) of mMRIand multimodal fusion imaging 18F-Choline-PETMRI 18F-Fluoride-PETCT provided the highest DR (detecting all 9patients affected by bone metastases) which was found to besignificantly different from that of CeCT (119875 = 0034)
42 Lesion-Based Analysis Overall 133 lesions were detectedin our analysis 102 of which were found in the pelvis andlower abdominal quadrants Of these 79 were malignant(including local recurrences and lymph node and skeletalmetastases) and 54 were benign according to the standardof reference Specifically we detected 6 local recurrences 40pelvic lymph node metastases and 33 bone metastases Sixtyof these 79 lesions were found in the field-of-view (FOV) ofmMRI encompassing pelvis and lower abdominal quadrantsConsidering only the FOV of mMRI the overall accuracyof fused 18F-Choline-PETMRI 18F-Choline-PETCT CeCTand mMRI was 99 95 70 and 85 respectivelySensitivity specificity PPV and NPV of different diagnosticmodalities were as follows 100 98 98 and 100 forfused 18F-Choline-PETMRI 95 98 98 and 93 for18F-Choline-PETCT 50 100 100 and 58 for CeCT75 95 96 and 75 for mMRI
The accuracy sensitivity and NPV of fused 18F-Choline-PETMRI were significantly higher than those of bothmMRI(119875 lt 005) and CeCT (119875 lt 005) No differences in
BioMed Research International 5
Table 3 Lesion-based analysis and sensitivity in lesion detection according to different sites of recurrencemetastases (ie local recurrencelymph nodes and bone) obtained by mMRI 18F-Choline PETMRI CeCT and 18F-Choline PETCT
terms of specificity (119875 gt 005) and PPV (119875 gt 005)were observed between the different diagnostic modalitiesA lesion-based analysis to determine the sensitivity of eachmodality in detecting recurrent lesions according to differentanatomical locations (ie local recurrence lymph nodes andbone metastases) was also performed these results are sum-marized in Table 3 18F-Choline-PETMRI was more usefulin detecting local relapse identifying more local recurrences(66 100) than 18F-Choline-PETCT (46 67) Two casesof local recurrence are illustrated in Figures 1 and 2 Howeverthe statistical difference between these two modalities wasnot significant owing to the low number of local recurrences(119875 = 045) Fused 18F-Choline-PETMRI showed signifi-cantly higher sensitivity in locating lymph node metastasesthan mMRI (119875 = 00002) and CeCT (119875 lt 00001) Onecase is illustrated in Figure 3 On the other handmultimodal-ity fusion 18F-Choline-PETMRI and 18F-Choline-PETCTdetected the same number of lymph node metastases Withregard to whole-body assessment we compared 18F-Choline-PETCT CeCT and 18F-Fluoride-PETCT in terms of theirability to detect bonemetastases Two cases of skeletal metas-tases are illustrated in Figures 4 and 5 The data regardingsensitivity are summarized in Table 4
5 Correlation between ADC Valuesand SUV-max
With regard to local recurrences we found a high and sta-tistically significant inverse correlation between ADC value(74 times 10minus4 plusmn 2 times 10minus4mm2s median 92 times 10minus4 [74 times10minus4ndash132 times 10minus3]) and SUV-max (33 plusmn 13 median 39 [14ndash48]) (r = minus083 119875 = 004) With regard to lymph noderecurrences we found a moderate and statistically significantinverse correlation between ADC value (14 times 10minus3plusmn 11 times10minus3mm2s median 98 times 10minus3 [12 times 10minus4ndash41 times 10minus3]) andSUV-max (7 plusmn 41 median 64 [16ndash14]) (r = minus06 119875 = 002)
6 Discussion
In this pilot study we used different morphologicaland functional imaging modalities (ie mMRI CeCT18F-Choline-PETCT 18F-Fluoride-PETCT and fused18F-Choline-PETMRI) to prospectively examine a smallhomogeneous cohort of 21 PC patients with biochemicalrecurrence after first-line EBRT The clinical implementationof 18F-Choline-PETCT and mMRI in assessing recurrentPC after EBRT is currently yielding encouraging results
6 BioMed Research International
(a) (b) (c)
(d) (e) (f)
Figure 1 72-year-oldman with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense focalarea close to the midline (arrow) The ADCmap (b) demonstrates that the nodular area (arrow) has significantly lower ADC values than thesurrounding parenchyma The wash-in perfusion map (c) shows a high wash-in rate (arrow) On the 18F-Choline-PETCT axial image (d) adoubtful PET-positive focus (arrow) is appreciable while the lesion is not detectable on CeCT axial image (e) Fused 18F-Choline-PETMRIimage (f) demonstrates precise correspondence between PET-positive focus and MRI finding (arrow)
(a) (b)
(c) (d)
Figure 2 75-year-old man with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense area(arrow) in the posterior left lateral aspect of the prostate apex The ADC map (b) demonstrates that the hypointense nodular area has lowerADC values than the surrounding parenchyma (arrow) On 18F-Choline-PET axial scan (c) a well-defined PET-positive focus is appreciable(arrow) Fused 18F-Choline-PETMRI image (d) shows exact correspondence between PET-positive focus and MRI finding (arrow)
BioMed Research International 7
(a) (b) (c)
(d) (e)
Figure 3 78-year-old man with a bone metastasis in the right proximal femur The bone lesion (arrow) is well detectable on STIR (a) 18F-Fluoride-PETCT (b) and fused 18F-Choline-PETMRI axial images while it is not visible on T2-weighted (d) and CeCT (e) axial images
(a) (b) (c)
Figure 4 82-year-old man with a bone metastasis in the posterior arch of the left 10th rib The lesion (arrow) is not definitely appreciableon the CeCT axial image (a) and is not detectable on the 18F-Choline-PET axial scan (b) On the 18F-Fluoride-PETCT axial image (c) theskeletal metastasis is well detectable
[7 16] and this growing evidence is confirmed by the dataof our study showing high DRs for both modalities (ie 76and 81 resp) Multimodal fusion imaging between 18F-Choline-PETCT and mMRI (fused 18F-Choline-PETMRI)yielded an even better DR (ie 86) thus underscoringthat multimodal coregistration synchronized navigationand combined interpretation are more valuable than theindividual separate assessment of different diagnostic
techniques Only preliminary studies [11 12] are available onthe simultaneous acquisition of PET andMRIwith integratedPETMRI scanners on PC and to date only one paper hasaddressed the issue of multimodal fusion PETMRI imaging(with the two modalities acquired at separate times withdifferent scanners) in the assessment of 17 patients withprimary prostate cancer [17] To the best of our knowledgeour study was the first to investigate the diagnostic value of
8 BioMed Research International
(a) (b) (c)
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
interslice gap 04mm in plane resolution 06 times 06mm) witha large field of viewwere first oriented in the three orthogonalplanes (sagittal axial and coronal) without fat saturationenabling identification of the prostate gland and pelvic lymphnode stations High-resolution oblique axial and coronalscans (slice thickness 3ndash35mm interslice gap 03mm) werefurther oriented perpendicular and parallel to the rectopro-static plane in order to avoid misinterpretation due to partialvolume effects Diffusion-weighted imaging (DWI) sequence(b 1000 sm2 TR 3400 TE 763 bandwidth 250 kHz FOV 40times 40 slice thickness 40mm interslice gap 04mm matrix128 times 128 number of excitations 6 and in plane resolution 15times 15mm) was acquired in the axial plane using same slicelocations of the first FSE T2w sequence Dynamic contrast-enhancedMRI (DCE-MRI) was acquired during intravenousinjection of the paramagnetic contrast medium with a flowrate of 3mLs A 3-dimensional spoiled gradient echo fatsaturated T1-weighted (LAVA) pulse sequence was repeatedin the axial plane 27 times with a temporal resolution of12 s during the injection of a single dose of contrast agentAn axial STIR sequence (TR 5000ms TE 801ms inversiontime 150ms thickness 5mm interslice gap 05mm matrix256 times 256) was performed to detect focal bone lesions andfor comparingmMRIwith PET techniques (ie 18F-Choline-PETCT and 18F-NaF PETCT) in the detection of bonerecurrence Antiperistaltic drugs were given for minimizingmotion artifacts due to intestinal peristalsis at the beginningof each mMRI examination
25 Fused 18F-Choline-PETMRI Multimodal imagingcoregistration fusion and synchronized navigation wereperformed using a novel dedicated software developed forresearch purposes (Quanta Prostate Camelot BiomedicalSystems srl Genoa Italy) This software was developedfor aiding multiparametric MRI (mMRI) interpretation andreporting as well as multimodal MRIPET coregistrationQuanta Prostate is able to simultaneously display differentMRI datasets allowing calculation of color-coded ADCmaps from DWI sequences and wash-inwash-out rate mapsfrom time-intensity curves of DCE-MRI Color-coded ADCand perfusion maps can be overlapped on T2w images andexamined with different levels of transparency Using QuantaProstate a deformable registration technique (employingnonlinear transformation and spatially varying deformablemodels) is applied for MRIPET coregistration in order tocompensate for changes in patient positioning and localdeformations between different imaging datasets (eg dueto varying degrees of filling of the urinary bladder) OnceMRIPET coregistration is performed the operator canperform quantitative measurements (ADC and SUV-maxvalues) by drawing a ROI on the currently selected ADC orSUV map
3 Image Interpretation
31 18F-Choline-PETCT and 18F-Fluoride-PETCT 18F-Choline-PETCT and 18F-Fluoride-PETCT studies were in-terpreted visually and semiquantitatively using themaximum
standardized uptake value (SUV-max) on a patient-by-patient and lesion-by-lesion basis using the above mentioneddedicated software to review fused PETCT imagesHowever no SUV-max cut-off value have been introducedand SUV was calculated for each lesion just to support visualinterpretation
On 18F-Choline-PETCT any focal and nonphysiologicaluptake corresponding to prostate parenchyma abdominaland pelvic lymph nodes and bone was considered as patho-logical
On 18F-Fluoride-PETCT bone lesions were consideredto be malignant if a high and focal 18F-Fluoride uptake wasdetected without any morphological changes on CT or ahigh and focal 18F-Fluoride uptake was associated to typicalmorphological changes on CT
32 Multiparametric MRI All mMRI were reviewed on adedicated workstation on (Advantage Workstation 46 Gen-eral Electric Medical Systems) using a tool for mMRI visual-ization and reporting A definitive diagnosis of cancer recur-rence (ie local lymph nodal and skeletal recurrence) wasformulated after examining eachMRI examination reportingthe number of lymph nodal and skeletal lesions Findingsindicative of local recurrence were identified accordingto ESUR prostate MR guidelines 2012 considering thatradiation-induced fibrosis and shrinkage of the gland mayoften hinder lesion detection [15] DWI sequence was exam-ined by generating anADCmap searching for intraglandularnodular foci characterized by restriction of water diffusionrelative to the surrounding prostate parenchyma ADC valueof the glandular area affected by recurrent disease was regis-tered and compared with the corresponding SUV-max valueof 18F-Choline-PETCT On DCE-MRI sequences prostatecancer recurrence was recognized as an early enhancing areain contrast to the surrounding glandular tissue A quantitativewash-in perfusionmapwas generated for aiding the detectionof hypervascularized foci within the prostate gland Thefollowing morphological and size criteria were used to definea metastatic lymph node short axis diameter gt10mm for anoval lymph node and diameter gt8mm for a round lymphnode The ADC value of the most PET-positive lymph nodeof each lymph nodal station involved by recurrent diseasewas registered and compared to the SUV-max value of 18F-Choline-PETCT Axial STIR sequence was employed tosearch bone metastases that appear as hyperintense focallesions within the spongy or cortical bone compartments
33 Contrast-Enhanced CT On CT scans the separationbetween the prostate and the levator ani muscle is poorlydefined and intraprostatic anatomy is not well demonstratedOnly the following morphologic criteria were applied fordefining local recurrence prostate enlargement with focalcapsule bulging nodular areas of inhomogeneous contrastenhancement within the peripheral gland sign of extracap-sular extension Bone metastases were considered to havean osteosclerotic or mixed (ie osteolytic and osteosclerotic)appearance
4 BioMed Research International
Table 2 Patient-based analysis DR was calculated for each single diagnostic modality in each site of disease
34 Multimodal Fusion Imaging On 18F-Choline-PETMRIany focus of nonphysiological uptake corresponding to anysuspected mMRI finding in prostate gland was consideredsuggestive for local recurrence Any focal uptake correspond-ing to mMRI detectable abdominal and pelvic lymph nodeswas considered as lymph node metastasis Any focal 18F-Choline bone uptake corresponding or not to a pathologicalfinding on mMRI was considered as bone metastasis
35 Standard of Reference CeCT and mMRI at 12 monthsserved as the standard of reference for the final discrimina-tion between true positive true negative false positive andfalse negative results Further available follow-up informationwas provided by response to salvage therapy laboratoryteststumourmarkers US-guided transrectal prostate biopsyand other imaging studies (X-ray studies and bone scans)Patients and lesions were considered true negative if follow-up cross-sectional imaging studies and transrectal ultrasoundwere both negative and the patients had stable PSA valuesA median clinical and imaging follow-up time of 14 months(range 12ndash18) was available for each patient
Histopathologic confirmation was available in 3 out of 5patients showing only local recurrence and in one out of sixpatients affected by lymph node metastases
36 Statistical Analysis No specific sample size calculationwas performed given the pilot nature of the study Cate-gorical data were summarised as number (percentage) ofsubjectslesions continuous data were summarised as meanstandard deviation median and range The normal distribu-tion of datasets of different variables was assessed bymeans oftheDrsquoAgostino-Pearson testWhendatasets did not follow thenormal distribution nonparametric tests were used insteadof parametric ones The degree of correlation between ADCand -max values for local and lymph node recurrence wasassessed by the Spearman rank test The diagnostic perfor-mance of different diagnostic modalities (ie mMRI CeCT18F-Choline-PETCT and 18F-NaF PETCT) for determiningthe presence of recurrent disease was calculated using 2 times 2tables Sensitivity specificity positive and negative predictivevalues and overall diagnostic accuracy were calculatedThe diagnostic performances of different modalities werecompared by means of the Fisher exact test for proportionswith level of statistical significance set at 005
4 Results
41 Patient-Based Analysis Fused 18F-Choline-PETMRIwas positive in 18 of 21 patients with an overall detection rate(DR) of 86 Local relapse was detected in 6 patients oneof whom was also affected by bone metastases Lymph nodemetastases were detected in 6 patients two of whom also hadbone involvement Six patients showed only bonemetastasesThe DR of 18F-Choline-PETCT CeCT and mMRI was 76(1621 patients) 43 (921 patients) and 81 (1721 patients)respectively The difference between the DR of multimodalfusion imaging 18F-Choline-PETMRI and that of CeCT wasstatistically significant (119875 = 0016) while comparing mMRIand 18F-Choline-PETCT with CeCT it only tended to besignificant (119875 = 0093 for bothmodalities) No significant dif-ference was found between 18F-Choline-PETMRI and 18F-Choline-PETCT nor between 18F-Choline-PETMRI andmMRI (119875 = 067 for both comparisons) Table 2 shows theDRs recorded when the different sites of PC recurrence wereconsidered separately Considering all skeletal metastasesincluding those beyond the field-of-view (FOV) of mMRIand multimodal fusion imaging 18F-Choline-PETMRI 18F-Fluoride-PETCT provided the highest DR (detecting all 9patients affected by bone metastases) which was found to besignificantly different from that of CeCT (119875 = 0034)
42 Lesion-Based Analysis Overall 133 lesions were detectedin our analysis 102 of which were found in the pelvis andlower abdominal quadrants Of these 79 were malignant(including local recurrences and lymph node and skeletalmetastases) and 54 were benign according to the standardof reference Specifically we detected 6 local recurrences 40pelvic lymph node metastases and 33 bone metastases Sixtyof these 79 lesions were found in the field-of-view (FOV) ofmMRI encompassing pelvis and lower abdominal quadrantsConsidering only the FOV of mMRI the overall accuracyof fused 18F-Choline-PETMRI 18F-Choline-PETCT CeCTand mMRI was 99 95 70 and 85 respectivelySensitivity specificity PPV and NPV of different diagnosticmodalities were as follows 100 98 98 and 100 forfused 18F-Choline-PETMRI 95 98 98 and 93 for18F-Choline-PETCT 50 100 100 and 58 for CeCT75 95 96 and 75 for mMRI
The accuracy sensitivity and NPV of fused 18F-Choline-PETMRI were significantly higher than those of bothmMRI(119875 lt 005) and CeCT (119875 lt 005) No differences in
BioMed Research International 5
Table 3 Lesion-based analysis and sensitivity in lesion detection according to different sites of recurrencemetastases (ie local recurrencelymph nodes and bone) obtained by mMRI 18F-Choline PETMRI CeCT and 18F-Choline PETCT
terms of specificity (119875 gt 005) and PPV (119875 gt 005)were observed between the different diagnostic modalitiesA lesion-based analysis to determine the sensitivity of eachmodality in detecting recurrent lesions according to differentanatomical locations (ie local recurrence lymph nodes andbone metastases) was also performed these results are sum-marized in Table 3 18F-Choline-PETMRI was more usefulin detecting local relapse identifying more local recurrences(66 100) than 18F-Choline-PETCT (46 67) Two casesof local recurrence are illustrated in Figures 1 and 2 Howeverthe statistical difference between these two modalities wasnot significant owing to the low number of local recurrences(119875 = 045) Fused 18F-Choline-PETMRI showed signifi-cantly higher sensitivity in locating lymph node metastasesthan mMRI (119875 = 00002) and CeCT (119875 lt 00001) Onecase is illustrated in Figure 3 On the other handmultimodal-ity fusion 18F-Choline-PETMRI and 18F-Choline-PETCTdetected the same number of lymph node metastases Withregard to whole-body assessment we compared 18F-Choline-PETCT CeCT and 18F-Fluoride-PETCT in terms of theirability to detect bonemetastases Two cases of skeletal metas-tases are illustrated in Figures 4 and 5 The data regardingsensitivity are summarized in Table 4
5 Correlation between ADC Valuesand SUV-max
With regard to local recurrences we found a high and sta-tistically significant inverse correlation between ADC value(74 times 10minus4 plusmn 2 times 10minus4mm2s median 92 times 10minus4 [74 times10minus4ndash132 times 10minus3]) and SUV-max (33 plusmn 13 median 39 [14ndash48]) (r = minus083 119875 = 004) With regard to lymph noderecurrences we found a moderate and statistically significantinverse correlation between ADC value (14 times 10minus3plusmn 11 times10minus3mm2s median 98 times 10minus3 [12 times 10minus4ndash41 times 10minus3]) andSUV-max (7 plusmn 41 median 64 [16ndash14]) (r = minus06 119875 = 002)
6 Discussion
In this pilot study we used different morphologicaland functional imaging modalities (ie mMRI CeCT18F-Choline-PETCT 18F-Fluoride-PETCT and fused18F-Choline-PETMRI) to prospectively examine a smallhomogeneous cohort of 21 PC patients with biochemicalrecurrence after first-line EBRT The clinical implementationof 18F-Choline-PETCT and mMRI in assessing recurrentPC after EBRT is currently yielding encouraging results
6 BioMed Research International
(a) (b) (c)
(d) (e) (f)
Figure 1 72-year-oldman with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense focalarea close to the midline (arrow) The ADCmap (b) demonstrates that the nodular area (arrow) has significantly lower ADC values than thesurrounding parenchyma The wash-in perfusion map (c) shows a high wash-in rate (arrow) On the 18F-Choline-PETCT axial image (d) adoubtful PET-positive focus (arrow) is appreciable while the lesion is not detectable on CeCT axial image (e) Fused 18F-Choline-PETMRIimage (f) demonstrates precise correspondence between PET-positive focus and MRI finding (arrow)
(a) (b)
(c) (d)
Figure 2 75-year-old man with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense area(arrow) in the posterior left lateral aspect of the prostate apex The ADC map (b) demonstrates that the hypointense nodular area has lowerADC values than the surrounding parenchyma (arrow) On 18F-Choline-PET axial scan (c) a well-defined PET-positive focus is appreciable(arrow) Fused 18F-Choline-PETMRI image (d) shows exact correspondence between PET-positive focus and MRI finding (arrow)
BioMed Research International 7
(a) (b) (c)
(d) (e)
Figure 3 78-year-old man with a bone metastasis in the right proximal femur The bone lesion (arrow) is well detectable on STIR (a) 18F-Fluoride-PETCT (b) and fused 18F-Choline-PETMRI axial images while it is not visible on T2-weighted (d) and CeCT (e) axial images
(a) (b) (c)
Figure 4 82-year-old man with a bone metastasis in the posterior arch of the left 10th rib The lesion (arrow) is not definitely appreciableon the CeCT axial image (a) and is not detectable on the 18F-Choline-PET axial scan (b) On the 18F-Fluoride-PETCT axial image (c) theskeletal metastasis is well detectable
[7 16] and this growing evidence is confirmed by the dataof our study showing high DRs for both modalities (ie 76and 81 resp) Multimodal fusion imaging between 18F-Choline-PETCT and mMRI (fused 18F-Choline-PETMRI)yielded an even better DR (ie 86) thus underscoringthat multimodal coregistration synchronized navigationand combined interpretation are more valuable than theindividual separate assessment of different diagnostic
techniques Only preliminary studies [11 12] are available onthe simultaneous acquisition of PET andMRIwith integratedPETMRI scanners on PC and to date only one paper hasaddressed the issue of multimodal fusion PETMRI imaging(with the two modalities acquired at separate times withdifferent scanners) in the assessment of 17 patients withprimary prostate cancer [17] To the best of our knowledgeour study was the first to investigate the diagnostic value of
8 BioMed Research International
(a) (b) (c)
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
34 Multimodal Fusion Imaging On 18F-Choline-PETMRIany focus of nonphysiological uptake corresponding to anysuspected mMRI finding in prostate gland was consideredsuggestive for local recurrence Any focal uptake correspond-ing to mMRI detectable abdominal and pelvic lymph nodeswas considered as lymph node metastasis Any focal 18F-Choline bone uptake corresponding or not to a pathologicalfinding on mMRI was considered as bone metastasis
35 Standard of Reference CeCT and mMRI at 12 monthsserved as the standard of reference for the final discrimina-tion between true positive true negative false positive andfalse negative results Further available follow-up informationwas provided by response to salvage therapy laboratoryteststumourmarkers US-guided transrectal prostate biopsyand other imaging studies (X-ray studies and bone scans)Patients and lesions were considered true negative if follow-up cross-sectional imaging studies and transrectal ultrasoundwere both negative and the patients had stable PSA valuesA median clinical and imaging follow-up time of 14 months(range 12ndash18) was available for each patient
Histopathologic confirmation was available in 3 out of 5patients showing only local recurrence and in one out of sixpatients affected by lymph node metastases
36 Statistical Analysis No specific sample size calculationwas performed given the pilot nature of the study Cate-gorical data were summarised as number (percentage) ofsubjectslesions continuous data were summarised as meanstandard deviation median and range The normal distribu-tion of datasets of different variables was assessed bymeans oftheDrsquoAgostino-Pearson testWhendatasets did not follow thenormal distribution nonparametric tests were used insteadof parametric ones The degree of correlation between ADCand -max values for local and lymph node recurrence wasassessed by the Spearman rank test The diagnostic perfor-mance of different diagnostic modalities (ie mMRI CeCT18F-Choline-PETCT and 18F-NaF PETCT) for determiningthe presence of recurrent disease was calculated using 2 times 2tables Sensitivity specificity positive and negative predictivevalues and overall diagnostic accuracy were calculatedThe diagnostic performances of different modalities werecompared by means of the Fisher exact test for proportionswith level of statistical significance set at 005
4 Results
41 Patient-Based Analysis Fused 18F-Choline-PETMRIwas positive in 18 of 21 patients with an overall detection rate(DR) of 86 Local relapse was detected in 6 patients oneof whom was also affected by bone metastases Lymph nodemetastases were detected in 6 patients two of whom also hadbone involvement Six patients showed only bonemetastasesThe DR of 18F-Choline-PETCT CeCT and mMRI was 76(1621 patients) 43 (921 patients) and 81 (1721 patients)respectively The difference between the DR of multimodalfusion imaging 18F-Choline-PETMRI and that of CeCT wasstatistically significant (119875 = 0016) while comparing mMRIand 18F-Choline-PETCT with CeCT it only tended to besignificant (119875 = 0093 for bothmodalities) No significant dif-ference was found between 18F-Choline-PETMRI and 18F-Choline-PETCT nor between 18F-Choline-PETMRI andmMRI (119875 = 067 for both comparisons) Table 2 shows theDRs recorded when the different sites of PC recurrence wereconsidered separately Considering all skeletal metastasesincluding those beyond the field-of-view (FOV) of mMRIand multimodal fusion imaging 18F-Choline-PETMRI 18F-Fluoride-PETCT provided the highest DR (detecting all 9patients affected by bone metastases) which was found to besignificantly different from that of CeCT (119875 = 0034)
42 Lesion-Based Analysis Overall 133 lesions were detectedin our analysis 102 of which were found in the pelvis andlower abdominal quadrants Of these 79 were malignant(including local recurrences and lymph node and skeletalmetastases) and 54 were benign according to the standardof reference Specifically we detected 6 local recurrences 40pelvic lymph node metastases and 33 bone metastases Sixtyof these 79 lesions were found in the field-of-view (FOV) ofmMRI encompassing pelvis and lower abdominal quadrantsConsidering only the FOV of mMRI the overall accuracyof fused 18F-Choline-PETMRI 18F-Choline-PETCT CeCTand mMRI was 99 95 70 and 85 respectivelySensitivity specificity PPV and NPV of different diagnosticmodalities were as follows 100 98 98 and 100 forfused 18F-Choline-PETMRI 95 98 98 and 93 for18F-Choline-PETCT 50 100 100 and 58 for CeCT75 95 96 and 75 for mMRI
The accuracy sensitivity and NPV of fused 18F-Choline-PETMRI were significantly higher than those of bothmMRI(119875 lt 005) and CeCT (119875 lt 005) No differences in
BioMed Research International 5
Table 3 Lesion-based analysis and sensitivity in lesion detection according to different sites of recurrencemetastases (ie local recurrencelymph nodes and bone) obtained by mMRI 18F-Choline PETMRI CeCT and 18F-Choline PETCT
terms of specificity (119875 gt 005) and PPV (119875 gt 005)were observed between the different diagnostic modalitiesA lesion-based analysis to determine the sensitivity of eachmodality in detecting recurrent lesions according to differentanatomical locations (ie local recurrence lymph nodes andbone metastases) was also performed these results are sum-marized in Table 3 18F-Choline-PETMRI was more usefulin detecting local relapse identifying more local recurrences(66 100) than 18F-Choline-PETCT (46 67) Two casesof local recurrence are illustrated in Figures 1 and 2 Howeverthe statistical difference between these two modalities wasnot significant owing to the low number of local recurrences(119875 = 045) Fused 18F-Choline-PETMRI showed signifi-cantly higher sensitivity in locating lymph node metastasesthan mMRI (119875 = 00002) and CeCT (119875 lt 00001) Onecase is illustrated in Figure 3 On the other handmultimodal-ity fusion 18F-Choline-PETMRI and 18F-Choline-PETCTdetected the same number of lymph node metastases Withregard to whole-body assessment we compared 18F-Choline-PETCT CeCT and 18F-Fluoride-PETCT in terms of theirability to detect bonemetastases Two cases of skeletal metas-tases are illustrated in Figures 4 and 5 The data regardingsensitivity are summarized in Table 4
5 Correlation between ADC Valuesand SUV-max
With regard to local recurrences we found a high and sta-tistically significant inverse correlation between ADC value(74 times 10minus4 plusmn 2 times 10minus4mm2s median 92 times 10minus4 [74 times10minus4ndash132 times 10minus3]) and SUV-max (33 plusmn 13 median 39 [14ndash48]) (r = minus083 119875 = 004) With regard to lymph noderecurrences we found a moderate and statistically significantinverse correlation between ADC value (14 times 10minus3plusmn 11 times10minus3mm2s median 98 times 10minus3 [12 times 10minus4ndash41 times 10minus3]) andSUV-max (7 plusmn 41 median 64 [16ndash14]) (r = minus06 119875 = 002)
6 Discussion
In this pilot study we used different morphologicaland functional imaging modalities (ie mMRI CeCT18F-Choline-PETCT 18F-Fluoride-PETCT and fused18F-Choline-PETMRI) to prospectively examine a smallhomogeneous cohort of 21 PC patients with biochemicalrecurrence after first-line EBRT The clinical implementationof 18F-Choline-PETCT and mMRI in assessing recurrentPC after EBRT is currently yielding encouraging results
6 BioMed Research International
(a) (b) (c)
(d) (e) (f)
Figure 1 72-year-oldman with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense focalarea close to the midline (arrow) The ADCmap (b) demonstrates that the nodular area (arrow) has significantly lower ADC values than thesurrounding parenchyma The wash-in perfusion map (c) shows a high wash-in rate (arrow) On the 18F-Choline-PETCT axial image (d) adoubtful PET-positive focus (arrow) is appreciable while the lesion is not detectable on CeCT axial image (e) Fused 18F-Choline-PETMRIimage (f) demonstrates precise correspondence between PET-positive focus and MRI finding (arrow)
(a) (b)
(c) (d)
Figure 2 75-year-old man with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense area(arrow) in the posterior left lateral aspect of the prostate apex The ADC map (b) demonstrates that the hypointense nodular area has lowerADC values than the surrounding parenchyma (arrow) On 18F-Choline-PET axial scan (c) a well-defined PET-positive focus is appreciable(arrow) Fused 18F-Choline-PETMRI image (d) shows exact correspondence between PET-positive focus and MRI finding (arrow)
BioMed Research International 7
(a) (b) (c)
(d) (e)
Figure 3 78-year-old man with a bone metastasis in the right proximal femur The bone lesion (arrow) is well detectable on STIR (a) 18F-Fluoride-PETCT (b) and fused 18F-Choline-PETMRI axial images while it is not visible on T2-weighted (d) and CeCT (e) axial images
(a) (b) (c)
Figure 4 82-year-old man with a bone metastasis in the posterior arch of the left 10th rib The lesion (arrow) is not definitely appreciableon the CeCT axial image (a) and is not detectable on the 18F-Choline-PET axial scan (b) On the 18F-Fluoride-PETCT axial image (c) theskeletal metastasis is well detectable
[7 16] and this growing evidence is confirmed by the dataof our study showing high DRs for both modalities (ie 76and 81 resp) Multimodal fusion imaging between 18F-Choline-PETCT and mMRI (fused 18F-Choline-PETMRI)yielded an even better DR (ie 86) thus underscoringthat multimodal coregistration synchronized navigationand combined interpretation are more valuable than theindividual separate assessment of different diagnostic
techniques Only preliminary studies [11 12] are available onthe simultaneous acquisition of PET andMRIwith integratedPETMRI scanners on PC and to date only one paper hasaddressed the issue of multimodal fusion PETMRI imaging(with the two modalities acquired at separate times withdifferent scanners) in the assessment of 17 patients withprimary prostate cancer [17] To the best of our knowledgeour study was the first to investigate the diagnostic value of
8 BioMed Research International
(a) (b) (c)
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
Table 3 Lesion-based analysis and sensitivity in lesion detection according to different sites of recurrencemetastases (ie local recurrencelymph nodes and bone) obtained by mMRI 18F-Choline PETMRI CeCT and 18F-Choline PETCT
terms of specificity (119875 gt 005) and PPV (119875 gt 005)were observed between the different diagnostic modalitiesA lesion-based analysis to determine the sensitivity of eachmodality in detecting recurrent lesions according to differentanatomical locations (ie local recurrence lymph nodes andbone metastases) was also performed these results are sum-marized in Table 3 18F-Choline-PETMRI was more usefulin detecting local relapse identifying more local recurrences(66 100) than 18F-Choline-PETCT (46 67) Two casesof local recurrence are illustrated in Figures 1 and 2 Howeverthe statistical difference between these two modalities wasnot significant owing to the low number of local recurrences(119875 = 045) Fused 18F-Choline-PETMRI showed signifi-cantly higher sensitivity in locating lymph node metastasesthan mMRI (119875 = 00002) and CeCT (119875 lt 00001) Onecase is illustrated in Figure 3 On the other handmultimodal-ity fusion 18F-Choline-PETMRI and 18F-Choline-PETCTdetected the same number of lymph node metastases Withregard to whole-body assessment we compared 18F-Choline-PETCT CeCT and 18F-Fluoride-PETCT in terms of theirability to detect bonemetastases Two cases of skeletal metas-tases are illustrated in Figures 4 and 5 The data regardingsensitivity are summarized in Table 4
5 Correlation between ADC Valuesand SUV-max
With regard to local recurrences we found a high and sta-tistically significant inverse correlation between ADC value(74 times 10minus4 plusmn 2 times 10minus4mm2s median 92 times 10minus4 [74 times10minus4ndash132 times 10minus3]) and SUV-max (33 plusmn 13 median 39 [14ndash48]) (r = minus083 119875 = 004) With regard to lymph noderecurrences we found a moderate and statistically significantinverse correlation between ADC value (14 times 10minus3plusmn 11 times10minus3mm2s median 98 times 10minus3 [12 times 10minus4ndash41 times 10minus3]) andSUV-max (7 plusmn 41 median 64 [16ndash14]) (r = minus06 119875 = 002)
6 Discussion
In this pilot study we used different morphologicaland functional imaging modalities (ie mMRI CeCT18F-Choline-PETCT 18F-Fluoride-PETCT and fused18F-Choline-PETMRI) to prospectively examine a smallhomogeneous cohort of 21 PC patients with biochemicalrecurrence after first-line EBRT The clinical implementationof 18F-Choline-PETCT and mMRI in assessing recurrentPC after EBRT is currently yielding encouraging results
6 BioMed Research International
(a) (b) (c)
(d) (e) (f)
Figure 1 72-year-oldman with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense focalarea close to the midline (arrow) The ADCmap (b) demonstrates that the nodular area (arrow) has significantly lower ADC values than thesurrounding parenchyma The wash-in perfusion map (c) shows a high wash-in rate (arrow) On the 18F-Choline-PETCT axial image (d) adoubtful PET-positive focus (arrow) is appreciable while the lesion is not detectable on CeCT axial image (e) Fused 18F-Choline-PETMRIimage (f) demonstrates precise correspondence between PET-positive focus and MRI finding (arrow)
(a) (b)
(c) (d)
Figure 2 75-year-old man with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense area(arrow) in the posterior left lateral aspect of the prostate apex The ADC map (b) demonstrates that the hypointense nodular area has lowerADC values than the surrounding parenchyma (arrow) On 18F-Choline-PET axial scan (c) a well-defined PET-positive focus is appreciable(arrow) Fused 18F-Choline-PETMRI image (d) shows exact correspondence between PET-positive focus and MRI finding (arrow)
BioMed Research International 7
(a) (b) (c)
(d) (e)
Figure 3 78-year-old man with a bone metastasis in the right proximal femur The bone lesion (arrow) is well detectable on STIR (a) 18F-Fluoride-PETCT (b) and fused 18F-Choline-PETMRI axial images while it is not visible on T2-weighted (d) and CeCT (e) axial images
(a) (b) (c)
Figure 4 82-year-old man with a bone metastasis in the posterior arch of the left 10th rib The lesion (arrow) is not definitely appreciableon the CeCT axial image (a) and is not detectable on the 18F-Choline-PET axial scan (b) On the 18F-Fluoride-PETCT axial image (c) theskeletal metastasis is well detectable
[7 16] and this growing evidence is confirmed by the dataof our study showing high DRs for both modalities (ie 76and 81 resp) Multimodal fusion imaging between 18F-Choline-PETCT and mMRI (fused 18F-Choline-PETMRI)yielded an even better DR (ie 86) thus underscoringthat multimodal coregistration synchronized navigationand combined interpretation are more valuable than theindividual separate assessment of different diagnostic
techniques Only preliminary studies [11 12] are available onthe simultaneous acquisition of PET andMRIwith integratedPETMRI scanners on PC and to date only one paper hasaddressed the issue of multimodal fusion PETMRI imaging(with the two modalities acquired at separate times withdifferent scanners) in the assessment of 17 patients withprimary prostate cancer [17] To the best of our knowledgeour study was the first to investigate the diagnostic value of
8 BioMed Research International
(a) (b) (c)
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
Figure 1 72-year-oldman with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense focalarea close to the midline (arrow) The ADCmap (b) demonstrates that the nodular area (arrow) has significantly lower ADC values than thesurrounding parenchyma The wash-in perfusion map (c) shows a high wash-in rate (arrow) On the 18F-Choline-PETCT axial image (d) adoubtful PET-positive focus (arrow) is appreciable while the lesion is not detectable on CeCT axial image (e) Fused 18F-Choline-PETMRIimage (f) demonstrates precise correspondence between PET-positive focus and MRI finding (arrow)
(a) (b)
(c) (d)
Figure 2 75-year-old man with biopsy-proven local PC recurrence after EBRT T2-weighted axial image (a) demonstrates a hypointense area(arrow) in the posterior left lateral aspect of the prostate apex The ADC map (b) demonstrates that the hypointense nodular area has lowerADC values than the surrounding parenchyma (arrow) On 18F-Choline-PET axial scan (c) a well-defined PET-positive focus is appreciable(arrow) Fused 18F-Choline-PETMRI image (d) shows exact correspondence between PET-positive focus and MRI finding (arrow)
BioMed Research International 7
(a) (b) (c)
(d) (e)
Figure 3 78-year-old man with a bone metastasis in the right proximal femur The bone lesion (arrow) is well detectable on STIR (a) 18F-Fluoride-PETCT (b) and fused 18F-Choline-PETMRI axial images while it is not visible on T2-weighted (d) and CeCT (e) axial images
(a) (b) (c)
Figure 4 82-year-old man with a bone metastasis in the posterior arch of the left 10th rib The lesion (arrow) is not definitely appreciableon the CeCT axial image (a) and is not detectable on the 18F-Choline-PET axial scan (b) On the 18F-Fluoride-PETCT axial image (c) theskeletal metastasis is well detectable
[7 16] and this growing evidence is confirmed by the dataof our study showing high DRs for both modalities (ie 76and 81 resp) Multimodal fusion imaging between 18F-Choline-PETCT and mMRI (fused 18F-Choline-PETMRI)yielded an even better DR (ie 86) thus underscoringthat multimodal coregistration synchronized navigationand combined interpretation are more valuable than theindividual separate assessment of different diagnostic
techniques Only preliminary studies [11 12] are available onthe simultaneous acquisition of PET andMRIwith integratedPETMRI scanners on PC and to date only one paper hasaddressed the issue of multimodal fusion PETMRI imaging(with the two modalities acquired at separate times withdifferent scanners) in the assessment of 17 patients withprimary prostate cancer [17] To the best of our knowledgeour study was the first to investigate the diagnostic value of
8 BioMed Research International
(a) (b) (c)
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
Figure 3 78-year-old man with a bone metastasis in the right proximal femur The bone lesion (arrow) is well detectable on STIR (a) 18F-Fluoride-PETCT (b) and fused 18F-Choline-PETMRI axial images while it is not visible on T2-weighted (d) and CeCT (e) axial images
(a) (b) (c)
Figure 4 82-year-old man with a bone metastasis in the posterior arch of the left 10th rib The lesion (arrow) is not definitely appreciableon the CeCT axial image (a) and is not detectable on the 18F-Choline-PET axial scan (b) On the 18F-Fluoride-PETCT axial image (c) theskeletal metastasis is well detectable
[7 16] and this growing evidence is confirmed by the dataof our study showing high DRs for both modalities (ie 76and 81 resp) Multimodal fusion imaging between 18F-Choline-PETCT and mMRI (fused 18F-Choline-PETMRI)yielded an even better DR (ie 86) thus underscoringthat multimodal coregistration synchronized navigationand combined interpretation are more valuable than theindividual separate assessment of different diagnostic
techniques Only preliminary studies [11 12] are available onthe simultaneous acquisition of PET andMRIwith integratedPETMRI scanners on PC and to date only one paper hasaddressed the issue of multimodal fusion PETMRI imaging(with the two modalities acquired at separate times withdifferent scanners) in the assessment of 17 patients withprimary prostate cancer [17] To the best of our knowledgeour study was the first to investigate the diagnostic value of
8 BioMed Research International
(a) (b) (c)
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
Figure 5 79-year-old man with bilateral hypogastric lymph node metastases T2-weighted axial image (a) shows a right hypogastriclymphadenopathy (arrow) 18F-Choline-PET axial scan (b) demonstrates two areas of focal tracer uptake (arrows) Fused 18F-Choline-PETMRI axial image (c) demonstrates that the left focus of tracer uptake corresponded to a very tiny hypogastric lymphadenopathy (arrows)
this hybrid technique in the assessment of PC recurrenceafter EBRT Park et al [17] performed an intermodalityMRI11C-Choline-PET fusion process assisted by high-resolution ex vivo MRI of the prostate specimen which alsooffered the integration of registered histologic informationThey created a parameter represented by the simple quotientof SUV over ADC value in a volume of interest withinthe prostate parenchyma finding that the SUVADC ratiosignificantly increased the lesion-to-benign backgroundcontrast for tumours with Gleason grades ge3 + 4 In ourpaper we adopted an easier and more feasible coregistrationtechnique assisted by the new software Quanta Prostate(Camelot Biomedical Systems srl Genoa Italy) to integratemorphological functional and metabolic information fromdifferent imagingmodalities With regard to the lesion-basedanalysis 18F-Choline-PETMRI showed significantly higheraccuracy sensitivity and NPV than mMRI (119875 lt 005)and CeCT (119875 lt 005) Specifically 18F-Choline-PETMRIdetectedmore lymphnodemetastases thanmMRI andCeCTThis result may be due to the fact that only morphologicaland size criteria were adopted for defining a metastaticlymph node (ie short axis diameter gt10mm for an ovallymph node and diameter gt8mm for a round lymph node)on both mMRI and CeCT In a previous pilot study [13]on 14 PC patients Beer et al compared 11C-Choline-PETSUV with ADC values of pelvic lymph nodes suspectedfor metastatic involvement They found a moderate butsignificant inverse correlation between SUV and ADCvalues and a significant difference in mean ADC and SUVvalues between benign and malignant lymph nodes Ourresults confirmed this significant inverse correlation betweenSUV and ADC values However a major limitation ofDWI in PC is the lack of specificity of the ADC valuein discriminating between benign and malignant lymphnodes We did not find any significant difference in termsof diagnostic performance between 18F-Choline-PETMRIand 18F-Choline-PETCT but this latter technique was ableto identify only 46 cases of local relapse versus 66 withthe former technique Although the diagnostic value ofT2w imaging is hampered by radiation-induced fibrosis andshrinkage of the prostate functional MRI techniques (ieDWI sequences and DCE-MRI) are effective in the detection
of local PC recurrence When multimodal fusion imagingis used perfect matching between a focus of 18F-Cholineuptake and a suspicious mMRI finding on fused PETMRIimages may improve the diagnostic confidence of eachseparate diagnostic modality Despite the low number ofpatients included a significant inverse correlation was alsoobserved between ADC and SUV values in the case oflocal recurrent disease This supports the relationship inPC between the high cellularity expressed by ADC and themetabolic activity of phospholipid turnover expressed bySUV With regard to the detection of skeletal metastasesin pelvic bones fused 18F-Choline-PETMRI performedsignificantly better than CeCT (Table 4) In addition oncomparing CeCT 18F-Choline-PETCT and 18F-Fluoride-PETCT in the detection of bone metastases throughout theentire skeleton we found that the highest sensitivity wasobtained with 18F-Fluoride-PETCT However a significantdifference emerged only between 18F-Fluoride-PETCTand CeCT 18F-Choline-PETCT proved to be slightly lesssensitive than 18F-Fluoride-PETCT as previously reported[18] in which it failed to detect one small sclerotic ribmetastasis
Despite our encouraging results some limitations shouldbe noted As the number of patients in our studywas small nospecific sample size calculation was performed In additionsome questions may arise with regard to the referencestandard that we adopted Indeed no really independent toolfor classifying lymph node and bone lesions was availableand for logistic and ethical reasons histological confirmationof metastases was not obtained in themajority of cases How-ever as in two previous studies [10 16] clinical laboratoryand follow-up data were collectively considered and used as astandard of reference This type of multidisciplinary follow-up is generally accepted to confirm lymph node and bonemetastasesMoreover histological confirmationwas availablein 35 patients showing only local recurrence and in 16patients affected by only lymph node metastases
7 Conclusions
According to our preliminary results 18F-Choline-PETMRIfusion imaging may be considered a feasible and promising
BioMed Research International 9
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
diagnostic tool for detecting PC recurrence in patients show-ing biochemical relapse after first-line treatment with EBRT
Conflict of Interests
The authors declare that there is no conflict of interestsregarding the publication of this paper
Authorsrsquo Contribution
Arnoldo Piccardo and Francesco Paparo equally contributedto paper preparation
References
[1] D B Chism A L Hanlon E M Horwitz S J Feigenberg andA Pollack ldquoA comparison of the single and double factor high-risk models for risk assignment of prostate cancer treated with3D conformal radiotherapyrdquo International Journal of RadiationOncology Biology Physics vol 59 no 2 pp 380ndash385 2004
[2] M Roach III G Hanks H Thames Jr et al ldquoDefiningbiochemical failure following radiotherapywith or without hor-monal therapy in men with clinically localized prostate cancerrecommendations of the RTOG-ASTRO Phoenix ConsensusConferencerdquo International Journal of Radiation Oncology Biol-ogy Physics vol 65 no 4 pp 965ndash974 2006
[3] S F Slovin A S Wilton G Heller and H I Scher ldquoTime todetectable metastatic disease in patients with rising prostate-specific antigen values following surgery or radiation therapyrdquoClinical Cancer Research vol 11 no 24 pp 8669ndash8673 2005
[4] R A Older M C Lippert S B Gay R A Omary and B JHillman ldquoComputed tomography appearance of the prostaticfossa following radical prostatectomyrdquoAcademic Radiology vol2 no 6 pp 472ndash474 1995
[5] A K Leventis S F Shariat and KM Slawin ldquoLocal recurrenceafter radical prostatectomy correlation of US features withprostatic fossa biopsy findingsrdquo Radiology vol 219 no 2 pp432ndash439 2001
[6] E Even-Sapir U Metser E Mishani G Lievshitz H Lermanand I Leibovitch ldquoThe detection of bone metastases in patientswith high-risk prostate cancer 99mTc-MDPplanar bone scintig-raphy single- and multi-field-of-view SPECT 18F-fluoride PETand 18F- Fluoride PETCTrdquoThe Journal of NuclearMedicine vol47 no 2 pp 287ndash297 2006
[7] L M Wu J R Xu H Y Gu et al ldquoRole of magnetic resonanceimaging in the detection of local prostate cancer recurrenceafter external beam radiotherapy and radical prostatectomyrdquoClinical Oncology vol 25 no 4 pp 252ndash264 2013
[8] M Cimitan R Bortolus S Morassut et al ldquo[18F]fluorocholinePETCT imaging for the detection of recurrent prostate cancerat PSA relapse experience in 100 consecutive patientsrdquo Euro-pean Journal of Nuclear Medicine and Molecular Imaging vol33 no 12 pp 1387ndash1398 2006
[9] D B Husarik R Miralbell M Dubs et al ldquoEvaluation of [18F]-choline PETCT for staging and restaging of prostate cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 2 pp 253ndash263 2008
[10] F Ceci P Castellucci T Graziani et al ldquo11C-Choline PETCTdetects the site of relapse in the majority of prostate cancerpatients showing biochemical recurrence after EBRTrdquoEuropean
Journal of Nuclear Medicine and Molecular Imaging vol 41 no5 pp 878ndash886 2014
[11] A Wetter C Lipponer F Nensa et al ldquoSimultaneous 18Fcholine positron emission tomographymagnetic resonanceimaging of the prostate initial resultsrdquo Investigative Radiologyvol 48 no 5 pp 256ndash262 2013
[12] A Wetter C Lipponer F Nensa et al ldquoEvaluation of the PETcomponent of simultaneous [18F]choline PETMRI in prostatecancer comparison with [18F]choline PETCTrdquo European Jour-nal of NuclearMedicine andMolecular Imaging vol 41 no 1 pp79ndash88 2014
[13] A J Beer M Eiber M Souvatzoglou et al ldquoRestricted waterdiffusibility as measured by diffusion-weighted MR imagingand choline uptake in 11C-choline PETCT are correlated inpelvic lymph nodes in patients with prostate cancerrdquoMolecularImaging and Biology vol 13 no 2 pp 352ndash361 2011
[14] A Heidenreich J Bellmunt M Bolla et al ldquoEAU guidelines onprostate cancermdashpart 1 screening diagnosis and treatment ofclinically localised diseaserdquo European Urology vol 59 no 1 pp61ndash71 2011
[15] J O Barentsz J Richenberg R Clements et al ldquoESUR prostateMRguidelines 2012rdquoEuropeanRadiology vol 22 no 4 pp 746ndash757 2012
[16] S Chondrogiannis M C Marzola A Ferretti et al ldquoRole of18F-choline PETCT in suspicion of relapse following definitiveradiotherapy for prostate cancerrdquo European Journal of NuclearMedicine and Molecular Imaging vol 40 no 9 pp 1356ndash13642013
[17] H Park D Wood H Hussain et al ldquoIntroducing parametricfusion PETMRI of primary prostate cancerrdquo The Journal ofNuclear Medicine vol 53 no 4 pp 546ndash551 2012
[18] M Beheshti R Vali P Waldenberger et al ldquoDetection of bonemetastases in patients with prostate cancer by 18F fluorocholineand 18F fluoride PET-CT a comparative studyrdquo EuropeanJournal of Nuclear Medicine and Molecular Imaging vol 35 no10 pp 1766ndash1774 2008
![Multi‑slicerepresentationallearning ......Suk et al. [7] MRI, PET, CSF Gray matter/ white matter segmentation, feature extrac-tion Stacked autoen-coder Extracted and fused high-level](https://static.documents.pub/doc/80x56/60d661f26c127e3f356d7c06/multiaslicerepresentationallearning-suk-et-al-7-mri-pet-csf-gray.jpg)
