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  • br changes other sequences might be needed Diffusion weighte


    changes, other sequences might be needed. Diffusion weighted MR imaging (DWI) visualises restriction in water mobility in tissue. Micro-environmental pathologic conditions such as the content of malignant tumour tissue change the water mobility and could be used as an early biomarker of response to CRT [16]. DWI is susceptible to T2 shine through effect for low b-values and to low signal to noise ratio (SNR) for relatively high b-values [17]. These effects can be mitigated and op-timal tissue characterisation can be achieved by quantifying the water mobility on a voxel basis by the so-called apparent HC 030031 coefficient (ADC) [17]. This parameter can be determined by fitting an exponential decay to the signal in various images with various b-values.
    With ADC-mapping, one can differentiate between malignant and non-malignant tissue in a region of interest with good test character-istics (sensitivity 96%, specificity 100%) [18]. Furthermore, alteration of mean ADC values (ΔADC) is higher in complete responders compared to partial and non-responders, and therefore could predict local recur-rence prior to brachytherapy [19–23].
    Since ADC mappings can chart micro-environmental changes in target areas, it might be used to reduce delineation uncertainties and to better differentiate between complete and partial/non-responders at the time of brachytherapy. Brachytherapy treatment could be adapted accordingly, by escalating the dose for partial/non-responders. In this study we have investigated the correlation of the ΔADC of the primary tumour during treatment to clinical outcome (disease recurrence), based on weekly MRI during external beam radiotherapy (EBRT), also taking into account FIGO stage and tumour volume. Furthermore, we have investigated mean ΔADC in pathologic lymph nodes and its cor-relation with primary tumour ΔADC.
    2. Materials and methods
    After approval of the institutional ethics review board, twenty pa-tients with cervical cancer that were eligible for definitive CRT (FIGO stage IB2-IVA and patients with pathological lymph nodes) were 
    included in a mono-centre imaging study (CeReMony). All patients received chemoradiation which consisted of EBRT 45 Gy in 25 daily fractions, with simultaneous integrated boost (SIB) for pathological lymph nodes to 57.5 Gy for para-aortic and common iliac nodes, and to 55 Gy for pathological lymph nodes within the pelvis. All fractions were delivered with a volumetric arc therapy (VMAT) technique. MRI-guided adaptive brachytherapy was given after two implantations in a total of four fractions (2 × 2) with high dose rate aiming at a CTVHR D90% > 90 Gy EQD210 according to the EMBRACE II protocol [9,10,13]. Patients underwent implantation with tandem and ovoid applicators compatible with the intracavitary-interstitial technique.
    2.2. Imaging protocol
    As part of the CeReMony study, all patients underwent three MRIs during EBRT treatment. The MRI protocol included three T2 weighted, multislice, turbo spin echo (TSE) sequences. For sagittal, coronal and transversal orientations, the repetition time/echo time (TR/TE) were respectively 4518/100 ms, 4649/100 ms, and 6332/100 ms; the TSE echo spacing/shot length 5.6/194 ms, 7.7/192 ms, and 7.7/192 ms. For these three MRI sequences the image resolution was 0.9 × 0.9 × 3 mm3, and the reconstructed voxel size was 0.5 × 0.5 × 3 mm3. Additionally, a DWI with fat suppression (Spectral Attenuated Inversion Recovery, SPAIR) was acquired using a single shot
    coefficient (ADC) map was determined by voxel-based, mono-ex-ponential fitting of the three diffusion weighted images acquired with the following b-values: 0, 200 and 800 s/mm2 with respectively 2, 2,
    and 4 signal averages (NSA).
    All MRI acquisitions were made on the same Philips 1,5 Tesla MRI scanner (MR-RT Ingenia, Philips Medical Systems, Best, The Netherlands) in supine treatment position using anterior (dStream Torso array) and integrated posterior coil arrays. A total of 4 MRI’s were made (MRI 1–4); the first MRI was performed before starting
    EBRT, the consecutive MRI’s were planned during treatment in week 1, 3 and 4 or in week 2, 3 and 4 of the EBRT treatment. The last MRI was made before brachytherapy implantation in week 4 of EBRT treatment. During follow-up routine T2 weighted MR images (without ADC map-ping) were made at 3 and 12 months after treatment, or when there was clinical suspicion for recurrence.
    2.3. Target definition and delineation
    On all MRI’s visible tumour (GTV) was separately delineated on T2
    sequence (GTVT2), and on the ADC-map (GTVADC) by one experienced radiation oncology resident (Fig. 1). GTVT2 is generally well visible on
    T2-weighted imaging and was delineated according to existing re-commendations [9,10]. Typically for GTVADC, the tumour showed a lower signal on ADC-map which was more homogenous than the sur-rounding tissue. Delineations were thoroughly checked and, if needed, adjusted after reaching consensus by a radiation oncologist with 20 years of experience within the field of gynaecological oncology. Furthermore, all lymph nodes that were considered metastatic (based on diagnostic MRI and PET-CT) by the multidisciplinary tumour board were delineated on the ADC map (GTVNx). Additionally three reference volumes (S1–3) were created in smooth muscle: one within the high dose EBRT (45 Gy) area (S1), one well below the caudal border of the planned radiotherapy field (S2), and one within the uninvaded part of the uterine corpus (S3).