Effect of radiochemotherapy on T2* MRI in HNSCC and its relation to FMISO PET derived hypoxia and FDG PET

Wiedenmann et al. Radiation Oncology (2018) 13:159 https://doi.org/10.1186/s13014-018-1103-1 RESEARCH Open Access Effect of radiochemotherapy on T2* MRI in HNSCC and its relation to FMISO PET derived hypoxia and FDG PET Nicole Wiedenmann1,4,5* , Hatice Bunea1,4,5, Hans C. Rischke1,3,4,5, Andrei Bunea1,4,5, Liette Majerus1,4,5, Lars Bielak2, Alexey Protopopov2, Ute Ludwig2, Martin Büchert2, Christian Stoykow3,4,5, Nils H. Nicolay1,4,5, Wolfgang A. Weber6, Michael Mix3,4,5, Philipp T. Meyer3,4,5, Jürgen Hennig2,4,5, Michael Bock2,4,5 and Anca L. Grosu1,4,5 Abstract Background: To assess the effect of radiochemotherapy (RCT) on proposed tumour hypoxia marker transverse relaxation time (T2*) and to analyse the relation between T2* and 18F-misonidazole PET/CT (FMISO-PET) and 18 F-fluorodeoxyglucose PET/CT (FDG-PET). Methods: Ten patients undergoing definitive RCT for squamous cell head-and-neck cancer (HNSCC) received repeat FMISO- and 3 Tesla T2*-weighted MRI at weeks 0, 2 and 5 during treatment and FDG-PET at baseline. Gross tumour volumes (GTV) of tumour (T), lymph nodes (LN) and hypoxic subvolumes (HSV, based on FMISO-PET) and complementary non-hypoxic subvolumes (nonHSV) were generated. Mean values for T2* and SUVmean FDG were determined. Results: During RCT, marked reduction of tumour hypoxia on FMISO-PET was observed (T, LN), while mean T2* did not change significantly. At baseline, mean T2* values within HSV-T (15 ± 5 ms) were smaller compared to nonHSV-T (18 ± 3 ms; p = 0.051), whereas FDG SUVmean (12 ± 6) was significantly higher for HSV-T (12 ± 6) than for nonHSV-T (6 ± 3; p = 0.026) and higher for HSV-LN (10 ± 4) than for nonHSV-LN (5 ± 2; p ≤ 0.011). Correlation between FMISO PET and FDG PET was higher than between FMSIO PET and T2* (R2 for GTV-T (FMISO/FDG) = 0.81, R2 for GTV-T (FMISO/T2*) = 0.32). Conclusions: Marked reduction of tumour hypoxia between week 0, 2 and 5 found on FMISO PET was not accompanied by a significant T2*change within GTVs over time. These results suggest a relation between tumour oxygenation status and T2* at baseline, but no simple correlation over time. Therefore, caution is warranted when using T2* as a substitute for FMISO-PET to monitor tumour hypoxia during RCT in HNSCC patients. Trial registration: DRKS, DRKS00003830. Registered 23.04.2012. Keywords: Tumour hypoxia, T2*, Multiparametric MRI, FMISO PET, FDG PET, HNSCC Background In squamous cell carcinoma of the head and neck (HNSCC) assessment of the extent of tumour hypoxia under primary radiochemotherapy (RCT) is warranted to obtain an early prognostic marker and to define potential dose escalation volumes [1–14]. Positron emission tomography (PET) can be considered the gold standard method * Correspondence: 1 Department of Radiation Oncology, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany 4 German Cancer Consortium (DKTK), Partner Site Freiburg, Freiburg, Germany Full list of author information is available at the end of the article for hypoxia imaging using hypoxia-associated tracers such as [18F]-fluoromisonidazole (FMISO) and [18F]-fluoroazomycinarabinoside (FAZA) [15–18]. Magnetic resonance imaging (MRI) can be used to characterize tumour function in several ways: Gadolinium(Gd)-perfusion MRI analyzes the tumour perfusion using the dynamic signal change after contrast medium injection, while Blood Oxygen Level Dependent (BOLD) MRI aims at assessing oxygen consumption. The MRI apparent transverse relaxation time T2*, respectively its reciprocal the relaxation rate R2*, obtained from T2*-weighted MRI, have been proposed as a potential imaging biomarker and surrogate © The Author(s). 2018, corrected publication 2018. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wiedenmann et al. Radiation Oncology (2018) 13:159 for hypoxia PET [19–34]. A change in regional concentration of oxy- vs. deoxyhaemoglobin can result in a change in magnetic field homogeneity, which is leading to a signal change in T2*-weighted MR acquisitions. In the literature, controversial findings are reported for T2* at baseline and during RCT: T2*-weighted MRI has recently been compared to FMISO-PET in glioma patients [32] where it provided complementary information rather than spatial correlation. In cervix cancer patients Kim et al. studied BOLD MRI before and after RCT, and they report a correlation between tumour R2* pre-RCT with tumour size response but not with tumour volume response [29]. Li et al. identified tumour R2* before RCT as a significant prognostic factor for progression-free and overall survival [30]. In HNSCC patients undergoing RCT, Panek et al. examined T2* signal stability and reproducibility pre-RCT, and they found that T2* measurements are highly reproducible [23]. Min et al. and Wong et al. evaluated serial functional imaging including R2*/T2*weighted MRI in HNSCC during RCT and found no clear pattern for changes in R2* [33, 34]. Here, we assessed hypoxia by analyzing T2* as a measure of the deoxyhaemoglobin concentration and used T2-weighted sequences and Gd-contrast enhanced T1 sequences for morphological characterization and delineation of tumours and lymph node metastasis. The aim of our study was to examine the effect of RCT on T2* in HNSCC at an early and late time point during RCT and to analyse the relation between T2* and FMISO-PET. Serial imaging was scheduled before RCT and at week 2 and week 5 during RCT. Baseline 18F-fluorodeoxyglucose-PET/CT (FDG-PET) was included to optimize pretherapy staging and considered for image analysis. To our knowledge, this is the first study to combine T2*weighted MRI with FMISO-PET in HNSCC. Methods Patients, imaging schedule and treatment Thirty two patients (T2–4 N+) were enrolled for this prospective functional MRI and hypoxia PET/CT imaging study during definitive RCT for HNSCC. Patients were recruited from 08/2014 to 11/2015. RCT was administered for 7 weeks in daily fractions of 2 Gy to a total dose of 70 Gy to the primary tumour and macroscopic lymph node metastases and 50 Gy to the elective lymphatic drainage. Concurrent chemotherapy was administered once in weeks 1, 4, and 7 with cisplatin (100 mg/kg/d or adjusted to lower dose) or carboplatin in case of chronic renal insufficiency. Patients underwent serial FMISO-PET as previously described [7, 8] and MRI in weeks 0, 2 and 5. FDG-PET was conducted in week 0. From the total patient coh (...truncated)