Simultaneous PET/MRI Assessment Of Response To Cytotoxic .
View metadata, citation and similar papers at core.ac.ukbrought to you byCOREprovided by Archivio della ricerca - Università degli studi di Napoli Federico IIMed Oncol (2017) 34:18DOI 10.1007/s12032-016-0876-zSHORT COMMUNICATIONSimultaneous PET/MRI assessment of response to cytotoxicand hormone neo-adjuvant chemotherapy in breast cancer:a preliminary reportValeria Romeo1 Massimiliano D’Aiuto2 Giuseppe Frasci2 Massimo Imbriaco1Emanuele Nicolai3 Received: 11 December 2016 / Accepted: 21 December 2016 / Published online: 30 December 2016 Springer Science Business Media New York 2016Abstract The aim of this study was to assess the responseto cytotoxic and hormone neo-adjuvant chemotherapy infour patients with locally advanced breast cancer bysimultaneous PET/MRI. Four patients with locallyadvanced breast cancer underwent simultaneous PET/MRIof the breast using a 3 T Biograph mMR before and afterneo-adjuvant chemotherapy (two patients were treated withhormone-therapy and two patients were treated with cytotoxic chemotherapy). Morpho-structural tumoral featuresand tumor size were assessed; area value, metabolic (SUVand MTV) and functional (ADC, Ktrans, Ve, kep and iAUC)data were obtained by positioning regions of interest. Acomparison of all parameters between the pre- and posttreatment PET/MRI examinations and between the twodifferent therapeutic schedules was assessed. In patientstreated with cytotoxic chemotherapy and classified as PR,there was a significant reduction of post-treatment morphological, metabolic and functional parameters. In a& Valeria Romeovaleria.romeo@unina.itMassimiliano D’Aiutom.daiuto@istitutotumori.na.itGiuseppe Frascig.frasci@istitutotumori.na.itMassimo Imbriacomimbriaco@hotmail.comEmanuele Nicolaie.nicolai@sdn-napoli.it1Department of Advanced Biomedical Sciences, UniversityFederico II of Naples, Via S. Pansini, 5, 80123 Naples, Italy2Breast Department, National Cancer Institute of NaplesIRCCS ‘‘G. Pascale’’, Naples, Italy3IRCCS SDN, Naples, Italypatient treated with hormone therapy, classified as SD,there was an increase of all post-treatment perfusionparameters, a substantially stable ADC value and a poorreduction of lesion size and of maximum SUV (SUVmax)values; the last patient, treated with hormone therapy andclassified as PR, showed a significant reduction of lesionsize and SUVmax values with a reduction of perfusionparameters and substantially stable ADC values. Multiparametric evaluation with simultaneous PET/MRI couldbe a useful tool to assess the response to cytotoxic andhormone neo-adjuvant chemotherapy in patients withbreast cancer. Future studies in a larger cohort of patientsare warranted to confirm the results of this preliminarystudy.Keywords Simultaneous PET/MRI Breast cancer Neoadjuvant chemotherapyIntroductionPositron emission tomography/magnetic resonance imaging (PET/MRI) is emerging as a powerful tool in theassessment of response to treatment in oncologic patients,with the possibility to simultaneously collect morphologic,metabolic and functional parameters (diffusion and perfusion parameters) [1]. Since its high contrast resolution inbreast tissue, the use of MRI in combination with PET is apromising imaging technique for the evaluation of breasttumor extension, nodal involvement, for the detection ofdistant metastasis and for treatment monitoring [2, 3].Moreover, preliminary studies suggest that simultaneous18F-FDG and DCE MRI may aid in the assessment ofbreast tumor aggressiveness and metastatic potential [4].123
18Page 2 of 7Med Oncol (2017) 34:18In this short and preliminary report we specificallyevaluated the morphological, metabolic and functionalparameters in two groups of four patients with locallyadvanced breast cancer before and after neo-adjuvantchemotherapy (two patients were treated with hormonetherapy, while the other two patients were treated withcytotoxic chemotherapy), in order to assess the response totreatment and to compare the behavior of such parametersbetween the two groups.Materials and methodsPatient populationFour patients underwent simultaneous PET/MRI of thebreast 2 h after 18F-FDG injection using a 3 T BiographmMR (Siemens Healthcare, Erlangen, Germany) with afour-channel breast coil, before and after neo-adjuvantchemotherapy. Of these, two patients were treated withcytotoxic chemotherapy (Group 1), while the other twopatients were treated with hormone-therapy (Group 2).Post-treatment evaluation was conducted at the end of thesecond cycle of cytotoxic chemotherapy and after2 months from the beginning of hormone therapy. Clinicaland histological post-surgical data for each patient arereported in Table 1; in particular, there were two invasiveductal carcinoma (IDC), one invasive lobular carcinoma(ILC) and one invasive ductal/lobular carcinoma. Thestudy was approved by our Institutional Review Board andinformed consent was obtained from all individual participants included in the study.PET/MRI acquisitionA dose of 401 35 MBq of [18F]-FDG was injecteddepending on patient’s body weight. After an uptake period80 16 min, patients underwent PET/MRI examination.PET/MRI was performed on the Biograph mMR (Siemens Healthcare, Erlangen, Germany). This system consists of a 3T MRI scanner featuring high-performancegradient systems (45 mT/m) and a slew rate of 200 T/m/s.The coils, patient table and cables have been redesigned forPET/MRI in order to minimize their attenuation and, thus,to allow unimpaired PET acquisition with the coils inplace. A fully functional PET system, equipped with theavalanche photodiode technology, is embedded into themagnetic resonance gantry. The PET scanner has a spatialresolution of 4.1 mm (FWHM) at 1 cm and of 5.0 mm(FWHM) at 10 cm from the transverse FOV and a sensitivity of 11.72 kcps/MBq at the center of the FOV. Bedposition was established in order to get a full coverage ofthe breast region. After a correct positioning had beenensured, the combined PET/MRI acquisition started. First,a coronal 2-point Dixon 3-dimensional volumetric interpolated breath-hold T1-weighted MRI sequence wasacquired and used for the generation of attenuation mapsand for anatomic allocation of the PET results. The software of the MRI scanner automatically generated fourdifferent images: T1-weighted in-phase, T1-weighted outof-phase, water-only and fat-only. Simultaneously with thestart of the Dixon MRI sequence, PET acquisition startedensuring correct temporal and regional correspondencebetween MRI and PET data. The PET data acquisitionoccurred during the entire MR acquisition time, takingdelayed acquisition times and radioactive decay intoaccount.MRI-based attenuation correctionFor attenuation correction of the PET data from the PET/MR scanner, attenuation maps generated on the basis of theDixon MRI sequence were applied. The attenuation mapswere generated on the basis of the 2-point Dixon MRIsequences. This approach has recently been demonstratedto provide results comparable to those of conventionalattenuation correction by low-dose CT [5]. The procedurehas been implemented in the post-processing software ofthe scanner and operates automatically. The Dixon fat- andwater-weighted images were used to create an attenuationmap with four distinct tissue-classes: background, lungs,fat and soft tissue. The lungs were identified by connected-Table 1 Patient populationPatientAgeLocationHistological typeGradeER (%)PG (%)Ki67 tILCG285HER2 30100HormoneIDLC invasive ductal/lobular carcinoma, IDC invasive ductal carcinoma, ILC invasive lobular carcinoma, ER estrogen receptor, PG progesteronereceptor, NAC neo-adjuvant chemotherapy123
Med Oncol (2017) 34:18Page 3 of 7 18component analysis of the air in the inner part of the body.By application of a morphologic closing filter, virtual airartifacts induced by the absence of an MRI signal in cortical bone, heart and aorta (because of blood flow) werecorrected. Attenuation of the PET signal caused byinstrumentation such as the patient bed and the fixed MRIcoils is automatically integrated into the attenuation maps.MR acquisitionThe MRI protocol was performed with a dedicated breastcoil, including: Axial and coronal STIR (repetition time, echo time,inversion time TR/TE/TI 4220/61/220 ms);Axial diffusion-weighted imaging (DWI), a single-shotecho planar 2d SPAIR (TR/TE 9900/69 ms) usingthree b values: 0, 500 and 800 s/mm2.Perfusion (DCE) studies were obtained with intravenous administration of paramagnetic contrast agent(Magnevist, Bayer, Berlin, Germany) 0.2 ml/kg, a flowrate of 3.5 ml/s, after two pre-contrast transaxialT1Vibe with flip angles of 15 and 2 degrees followedby a t1vibe tra dynamic (TR/TE 5.37/1.78 ms) with50 measurements. Additionally, an axial isovolumetricVIBE FAT SAT axial and axial FFE FAT SAT T1 (TR/TE 8.7/4.3 ms) were acquired.Data processing and multiparametric analysisPET data obtained on PET/MR scanner were processed withreconstruction and correction algorithms. Emission datawere corrected for randoms, dead time, scatter and attenuation. A 3-dimensional attenuation-weighted ordered-subsetsexpectation maximization iterative reconstruction algorithm(AW OSEM 3D) was applied with three iterations and 21subsets, Gaussian smoothing of 4 mm in full width at halfmaximum and a zoom of 1.Two radiologists experienced in breast imaging (16 and8 years experience), and one nuclear medicine specialist(16 years experience) evaluated PET/MRI images in consensus. Response to treatment was assessed according to theRECIST and PERCIST criteria [6, 7] and classified as complete response (CR), partial response (PR), stable disease(SD) or progression disease (PD). Lesion size was measuredconsidering the maximum lesion diameter (mm), while thetumoral area (cm2) was quantified by positioning regions ofinterest (ROIs) over the tumoral lesions in the major diameterlesion slice; post-contrast T1-weighted and STIR-weightedimages were utilized to assist in the breast tumor outline.In PET images, regional tracer uptake was quantified bypositioning ROIs over the tumoral lesions at the level ofmaximum extension to obtain 2D maximal and meanstandardized uptake values (SUVmax 2D, SUVmean 2D); 3Dmaximal and mean standardized uptake values (SUVmax3D, SUVmean 3D, MTV) were obtained by positioning avolume-of-interest (VOI) over the tumoral lesions with athreshold of 30% of the maximum signal intensity (MTV30).Tumor detection, tumoral extension and infiltration ofneighboring structures were assessed mainly on MRdynamic sequences. Subsequently, the DCE-MR imageswere transferred for post-processing to a workstationrunning commercially available software for tissue perfusion estimation (Tissue 4D, Siemens Medical Systems,Germany). After motion correction and registration of thepre- and post-contrast acquisitions, T1 mapping wasautomatically performed and a freehand region-of-interestTable 2 Pre- and post-treatment morphological, metabolic and perfusion parametersParameterCytotoxic neo-adjuvant chemotherapyPt 1Pre-treatPt 1Post-treatPt 2Pre-treatHormone neo-adjuvant chemotherapyPt 2Post-treatPt 3Pre-treatPt 3Post-treatPt 4Pre-treatPt 4Post-treatTumor size (mm)8240372845387436Tumor area (cm2)27.186.584.833.2512.7811.613.36.36SUVmax 2D (KBq/ml)348.76122.67121015.53.17SUVmax 3D42.212.712.12.6715.1125.761.88MTV 0.701.190.662.091.030.91.010.99Ktrans meanVe 4186.8535.44459Kep mean92.723.32119.528.7743.4949.3330.4812.53iAUC mean518204552.9435.2237.13366143.35115.52Pre-treat pre-treatment, Post-treat post-treatment, SUV standard uptake volume, MTV metabolic tumor volume, ADC apparent diffusioncoefficient, iAUC initial area under the concentration curve123
18Page 4 of 7Med Oncol (2017) 34:18Fig. 1 Multiparametric evaluation of morphological (STIR and T1FS ? mdc), metabolic (PET) and functional (DWI, ADC, iAUC,Ktrans, kep, Ve) parameters in a 54-year old female (Pt 1) with aninfiltrating ductal/lobular carcinoma of the left breast before cytotoxicchemotherapy. A large tumoral mass with significant post-contrastenhancement, increase of 18FDG uptake, restricted diffusivity andincreased perfusion is appreciated(ROI) was plotted around the tumor including the neighboring structures. The pharmacokinetic modeling wasbased on a two compartment pharmacokinetic modelproposed by Toft and Kermode [8] that allows the calculation of the following parameters: the influx volumetransfer constant between vascular and extravascular/extracellular space (EES) (Ktrans), the efflux rate constantbetween vascular and EES (kep), the fractional volume ofEES (Ve) and the initial area under the concentration curve(iAUC), defined as a measure of the total amount ofcontrast agent delivered to and retained within the tumorduring the stated time period. Arterial input function (AIF)was related to gadolinium dose injected and was modeledby a bi-exponential function using an intermediate modeprovided by the software. For the subsequent tumor ROIanalysis, PET/MRI datasets (PET acquisition, axial T1post-contrast and axial STIR sequences, axial ADC mapand single perfusion maps for Ktrans, Ve, kep and iAUC)were evaluated into a unified measurements frameworkcustomized into Syngo.via software platform (SiemensMedical Solutions) allowing a visual comparison of themultiparametric data. AIF was calculated positioning aROI in the ascending aorta at the level of the right pulmonary artery. Freehand ROI area value, referred as thetumor size in the major diameter lesion slice, wasextracted for each patient. For multiparametric comparisons, the ROI outline was following drawn with sameposition and extent on each map to automatically extractmaximum and mean values for each parameter (SUVmaxand SUVmean for the PET; ADCmax and ADCmean for the123
Med Oncol (2017) 34:18diffusion; Ktrans, Ve, kep, and iAUC, respectively, max andmean for perfusion maps).Since the small sample size, no statistical analysis wasperformed and a direct comparison of the pre- and posttreatment values for each patient and between the twogroups of patients treated with the two different therapeutic schedules was carried out.ResultsA total of four lesions were observed on pre- and posttreatment PET/MR examinations. Mean size of lesions was59 mm (range 37–82 mm). Three cases (patients 1, 2 and4) were classified as PR according to both RECIST (lesionsize) and PERCIST (SUVmean values) criteria. In patient 3,Fig. 2 Multiparametric evaluation of morphological (STIR and T1FS ? mdc), metabolic (PET) and functional (DWI, ADC, iAUC,Ktrans, kep, Ve) of the same patient reported in Fig. 1 (Pt 1) after thePage 5 of 7 18there was a less pronounced reduction of tumor size(maximum diameter and tumor area) and 18-FDG uptake,consistent with SD. In detail, in patients 1 and 2, treatedwith cytotoxic chemotherapy and classified as PR, therewas a significant ([30%) post-treatment reduction of lesionsize, SUVmax values, perfusion parameters (except for Vemean) and a valuable increase of ADC values. In patient 3,treated with hormone therapy and classified as SD, therewas an increase of all post-treatment perfusion parameters,a substantially stable ADC value and a poor reduction oflesion size and SUVmax values (\30%); patient 4, treatedwith hormone therapy and classified as PR, showed a significant reduction of lesion size ([30%) and SUVmax values with a reduction of perfusion parameters (except for Vemean) and substantially stable ADC values.second cycle of cytotoxic chemotherapy. A significant reduction oftumor volume, FDG uptake, perfusion and an increased diffusivity arenow detected compared to the pre-treatment evaluation123
18Page 6 of 7All the values of pre- and post-treatment morphological,metabolic and perfusion parameters for each patient areshowed in Table 2.Examples of pre- and post-treatment multiparametricanalysis are, respectively, illustrated in Figs. 1 and 2.DiscussionA previous paper has shown the value of pre-treatmentDWI, DCE MRI parameters (Ktrans) and 18F-FDG PET/CTmeasure SUVmean as significant predictors for short-termresponse, assessed after two cycles of cytotoxic neo-adjuvant chemotherapy in breast cancer [9].Of note, imaging of tumor glucose metabolism with18F-fluorodeoxyglucose (18F-FDG) has gained widespreaduse to study the biological activity of tumor and overallprognosis of oncological patients [10]. ADC diffusionparameter provides microstructural information at thecellular level revealing area of restricted diffusivity,expression of high cell density; it has been demonstratedthat diffusion technique can detect microstructural changes (increase in ADC values) before tumor size reductionsare seen [11]. DCE parameters (iAUC, Ktrans, Kep and Ve)provide information about tumoral microvasculature, suchas tissue perfusion, capillary permeability and integrity,and they are considered as promising biomarkers tomonitor the effect of therapies that affect tumoral vascularization [12].In our study we have evaluated the clinical value ofsimultaneously acquired PET/MRI morphological, metabolic and functional parameters (i.e., SUVmax, SUVmean,MTV, ADC, iAUC, Ktrans, Kep and Ve) in a group offour patients for the assessment of response to neo-adjuvant cytotoxic chemotherapy and hormone therapy. Inparticular, we observed a significant reduction of posttreatment iAUC, Ktrans and Kep values and an increase ofpost-treatment ADC values in the two patients whounderwent cytotoxic chemotherapy (Pts 1 and 2). A lesspronounced but always significant reduction of the sameparameters was observed in patient 4 (PR). Conversely,we have not observed the same changes of both diffusionand perfusion post-treatment values in patient 3, classified as SD; in particular, the substantially stable ADCvalues and the paradoxal increase of all perfusionparameters were probably related to the poor response totreatment. The less pronounced reduction of ADC andperfusion parameters in patient 4, compared to patients 1and 2, could reflect the different mechanism of action ofthe 2 therapeutic schedules. A possible hypothesis couldbe the more direct cytotoxic effect of standardchemotherapy compared to hormone therapy resulting in123Med Oncol (2017) 34:18cell death with following reduction in cell density and/orrelease of pro-angiogenic cytokines. Conversely, hormonetherapy, determining an indirect effect on cell proliferation by the inhibition of estrogen receptors, could have aless pronounced effect on cell density and especially onneoangiogenesis.In conclusion, our preliminary results suggest thatmultiparametric evaluation with simultaneous PET/MRIcould be a useful tool to assess the response to cytotoxicand hormone neo-adjuvant chemotherapy in patients withbreast cancer. Future studies in a larger cohort of patientsare warranted to confirm the results of this study and tofurther evaluate the role of pharmacokinetic modeling insimultaneous PET/MRI imaging.Compliance with ethical standardsConflict of interest The authors declare that they have no conflict ofinterest.Ethical standards All procedures performed in studies involvinghuman participants were in accordance with the ethical standards ofthe institutional and/or national research committee and with the 1964Helsinki Declaration and its later amendments or comparable ethicalstandards.Informed consent Informed consent was obtained from all individual participants included in the study.References1. Rosenkrantz AB, Friedman K, Chandarana H, et al. Current statusof hybrid PET/MRI in oncologic imaging. AJR Am J Roentgenol.2016;206(1):162–72.2. Ho AM, Kalantari BN. PET/MRI: a new frontier in breast cancerimaging. Breast J. 2016;22(3):261–3.3. Tabouret-Viaud C, Botsikas D, Delattre BM, et al. PET/MR inbreast cancer. Semin Nucl Med. 2015;45(4):304–21.4. Margolis NE, Moy L, Sigmund EE, et al. Assessment ofaggressiveness of breast cancer using simultaneous 18F-FDGPET and DCE-MRI: preliminary observations. Clin Nucl Med.2016;41(8):e355–61.5. Eiber M, Martinez-Möller A, Souvatzoglou M, et al. Value of aDixon-based MR/PET attenuation correction sequence for thelocalization and evaluation of PET-positive lesions. Eur J NuclMed Mol Imaging. 2011;38(9):1691–701.6. Eisenhauer EA, Therasse P, Bogaerts J, et al. New responseevaluation criteria in solid tumours; Revised RECIST guideline(version 1.1). Eur J Cancer. 2009;45(2):228–47.7. O JH, Lodge MA, Wahl RL. Practical PERCIST: a simplifiedGuide to PET response criteria in solid tumors 1.0. Radiology.2016;280(2):576–84.8. Tofts PS, Kermode AG. Measurement of the blood-brain barrierpermeability and leakage space using dynamic MR imaging. 1.Fundamental concepts. Magn Reson Med. 1991;17(2):357–67.9. Tateishi Y, Miyake M, Nagaoka T, et al. 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classified as PR, showed a significant reduction of lesion size and SUV max values with a reduction of perfusion parameters and substantially stable ADC values. Multi-parametric evaluation with simultaneous PET/MRI could be a useful tool to assess the response to cytotoxic and hormone neo-adjuvant chem
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