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Tracking acute & chronic RT-induced fibrosis in cervical cancer using native & Late-Gadolinium-Enhancement Short-Inversion-Time (STIR) UTE

Khadija Sheikh¹, Junghoon Lee², Marc Morcos², Mohammad Rezae², Ravi T. Seethamraju³, Thomas Benkert⁴, Himanshu Bhat³, Henry R Halperin⁵, Bruce L. Daniel⁶, Akila N Viswanathan², and Ehud J Schmidt^2,5
¹Johns Hopkins School of Medicine, Washington, DC, United States, ²Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, MD, United States, ³Siemens Medical Solutions, Boston, MA, United States, ⁴MR Applications Predevelopment, Siemens Healthcare GmbH, Erlangen, Germany, ⁵Cardiology, Johns Hopkins School of Medicine, Baltimore, MD, United States, ⁶Radiology, Stanford University, Stanford, CA, United States

Synopsis

Imaging the temporal evolution of post-radiation fibrosis, which forms in irradiated tissues, supports quantifying tumor response and estimating surrounding-tissue injury. Five cervical cancer patients were scanned pre-external-beam-radiotherapy (EBRT), during and after EBRT, and 3-months post-EBRT and High-Dose-Rate (HDR) brachytherapy. A novel stack-of-spirals STIR-UTE sequence (TI=60ms) was used to image acute-fibrosis, utilizing collagen-bound-water’s short T2* and T1, and Late-Gadolinium-Enhancement (11-15min post-contrast) IR-UTE sequence (TI=200ms) to image chronic-fibrosis, utilizing scar’s slow-contrast-perfusion. Acute-fibrosis spatial-distribution followed EBRT and brachytherapy dose distributions. Over time, acute-fibrosis was converted into chronic-fibrosis. This is important as it forms the basis to guide radiation-therapy for re-irradiation and adaptive-planning.

Introduction

Radiation-induced fibrosis occurs following EBRT and brachytherapy intended to target malignancies. These regions are first infused with inflammatory fibroblasts (1,2), which deposit collagen layers that later remodel into denser matrices forming scars. Although this is essential for mechanically stabilizing the necrotic radiated regions, it leads to adverse effects (inelasticity, bleeding, fistula) when excessive. Medical interventions exist that attempt to alter the course of fibrosis accumulation and remodeling (2). Small-animal microscopy showed (3) that fibrosis forms early on during RT, with continued-growth and reduction in Extracellular Matrix (“packing”) accelerated in higher-dose regions. MRI can be used to detect chronic-fibrosis through Late-Gadolinium-enhancement (LGE) (4), T1-mapping (5), or dedicated contrast-agents (6), but methods to detect acute-fibrosis with ¹H MRI are lacking. We and others (7,8) previously demonstrated in collagen/aqueous-solution mixtures, similarly to water within bones (9), the ability to quantify small (>5%) collagen fractions with spiral Short-Inversion-Time Ultrashort echo-time (STIR-UTE) scans (7) that also have shorter spin-relaxation times that strongly attenuate fat and muscle (7), since both T2* and T1 of water bound to collagen are short (1.5T: ~750ms, ~80ms, respectively). In normal volunteers (7), collagen fractions in the pelvis corresponded to literature-reports. MRI is increasingly being used in RT-planning for accurate treatment delivery, while its use in therapy monitoring is emerging. In this pilot longitudinal study, we scanned 5 cervical-cancer patients during the course of radiation therapy (Figure 1), aiming to detect changes in the tumor/lymph-nodes and its surrounding organs-at-risk (OAR). We performed double-echo IR-UTE with TI=60ms and subtracted the 2nd-echo image to obtain the acute-fibrosis map, and also single-echo IR-UTE 11-13 min following contrast-administration, thereby replacing the conventional IR-Gradient-Echo LGE for chronic-fibrosis (scar) imaging. Maps of acute and chronic fibrosis at various stages of therapy were extracted, overlaid on diagnostic T2-weighted images and spatially registered with EBRT and brachytherapy dose distributions. Note that there exists a complimentary mechanism for the short T2*, short T1 hyper-enhanced voxels (e.g. acute-fibrosis) that will be demonstrated in STIR-UTE following radiation delivery, this being conversion of hemoglobin to the paramagnetic meta-hemoglobin. This mechanism delivers acute hyper-enhancement at locations where radio-frequency ablation lesions receive thermal doses exceeding necrosis thresholds (6), possibly playing a role here as a result of radiation’s (7) interaction with red-blood cells.

Methods

Subjects: Five cervical-cancer patients undergoing concurrent chemoradiation were included. Imaging was performed prior to radiation, after 33 Gy and 45 Gy EBRT radiation to the pelvis and lymph nodes, and 3-months after HDR (tandem and interstitial needles) brachytherapy was completed.
Image Acquisition: Imaging was performed in 1.5T MRIs (Siemens Aera and Sola) using the abdominal and spine arrays. Prototypical stack-of-spirals (Slice-direction centric-ordered phase-encoding) double-echo (TE=50,2690µs, TR/Ɵ=7ms/8°), STIR UTE with TI=60,80,100ms (TRelax=676-716ms), resolution=1.0x1.0x2.5mm³, 220spirals/slice, FOV=390mm, #Slices/vol=88, Readout-duration/spiral=1800ms, Averages=3, NUFFT reconstruction. The 2nd-echo was subtracted from the 1st-echo to obtain the short TE-only image. Conventional sequences (2D&3D T2w, 3D fatsatT1w pre- and post-contrast, DWI, DCE post-contrast), were also acquired.
Image Analysis: TI=60ms STIR-UTE was preferred due to a linear collagen-to-pixel-intensity relationship (7) and better fat-suppression. All images and dose distributions were rigidly registered to the treatment-planning CT acquired on the day of radiation treatment. Planning treatment volumes (PTV) and OAR contours were propagated onto the MR images (Figure 2). STIR-UTE images were segmented using a region-growing algorithm (RayStation 10A, Stockholm) and signal-intensity was normalized between successive scans based on the signal-intensity of articular cartilage of both femoral heads. For each time point, acute-fibrosis contours were segmented on the UTE TI=60ms subtraction images and chronic fibrosis contours were segmented on the late-gadolinium-enhanced UTE images (TI=200ms). The fibrosis contours were propagated onto the respective T2w images (Figure 2) and cropped to stay within the PTV (little acute-fibrosis was found outside). The mean dose of the acute fibrosis and chronic fibrosis were determined.

Results

Figure 3 correlates UTE features with the respective anatomy. Figure 4 shows EBRT and brachytherapy dose distributions and their correlation with acute fibrosis intensity levels for S2. Figure 5 shows acute (cyan) and chronic (pink) fibrosis overlaid on the T2 images acquired at the respective time points in two patients (S3, S4), with S3 displaying tumor recurrence at 3mths. The HDR isodose lines are shown in a colormap and the red contour indicates the 45Gy isodose line from the EBRT plan. For both patients, it is apparent that the acute fibrosis, initially covering the pelvic lymph nodes and much of the target, reduces in volume over time. Chronic fibrosis is observed in and around the uterus. There are strong regions of overlap between the acute and chronic fibrosis regions, suggesting conversion of acute to chronic fibrosis. For S3, mean brachytherapy doses of the acute and chronic regions were 220cGy and 411cGy, respectively. For S4, mean brachytherapy doses of the acute and chronic regions were 266cGy and 498cGy, respectively. The mean EBRT doses were 4600cGy.

Conclusions

In this feasibility study, a novel method to measure acute post-radiative fibrosis was evaluated in patients at 4 time points after EBRT and brachytherapy. It was compared to measurements of chronic fibrosis based on late Gadolinium-contrast perfusion. A reduction in acute-fibrosis and conversion to chronic-fibrosis was observed over time. Higher mean brachytherapy doses were observed in the chronic fibrosis regions.

Acknowledgements

NIH R01EB020667, R01HL094610, R01CA237005

References

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[3] Kotova SL, Timashev PS, Belkova GV, Kochueva MV, Babak KV,Timofeeva VA, Kiseleva EB, Vasilieva OO, Maslennikova AV and Solovieva AB, Early Effects of Ionizing Radiation on the Collagen Hierarchical Structure of Bladder and Rectum Visualized by Atomic Force Microscopy, Microscopy and Microanalysis 2018; 24:38-48

[4] Kim RJ, Fieno DS, Parrish TB, Harris K, Chen EL, Simonetti O, Bundy J, Finn JP, Klocke FJ, Judd RM. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation 1999; 100: 1992–2002.

[5] Messroghli DR, Radjenovic A, Kozerke S, Higgins DM, Sivananthan MU Modified Look‐Locker inversion recovery (MOLLI) for high‐resolution T1 mapping of the heart. Magn Reson Med 2004; 52:141–146.

[6] Caravan P, Das B, Dumas S, Epstein FH, , Helm PA, Jacques V, Kolodziej A, Shen L, Sun W-C, Zhang Z. Collagen‐Targeted MRI Contrast Agent for Molecular Imaging of Fibrosis. Angewandte Chemie 2007;119, 8319-8321

[7] Schmidt E J, Muradyan I, Benkert T, Bhat H, Kolandaivelu A, Halperin H R, Viswanathan A N. Imaging wound-healing related fibrosis using short inversion time ultra-short TE (STIR-UTE), Proceedings of the 27th Annual meeting of ISMRM, Montreal 2019, p. 0707

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[9] Ma Y-J, Jerban S, Jang H, Chang D, Chang EY and Du J (2020) Quantitative Ultrashort Echo Time (UTE) Magnetic Resonance Imaging of Bone: An Update. Front. Endocrinol. 11:567417 [10] Mugler JP III, Fielden SW, Meyer CH, Altes TA, Miller GW, Stemmer A, Kiefer B. Breath-hold UTE lung imaging using a stack-of-spirals acquisition. Proceedings of the 23rd Annual Meeting of ISMRM, Toronto, Canada 2015, p. 1476

Figures

Figure 1: Schematic of the MRI and CT scans acquired over the course of 6 months. Pre-treatment CT and MRI scans were followed by MRI during EBRT (patient receiving 33 Gy), after EBRT (patient receiving 45 Gy), 3 months following HDR brachytherapy, and 6 months following brachytherapy.

Figure 2: Planning CTs & MRI shown for representative patient (S1). First row displays planning CT with primary and nodal planning target volumes in orange and light purple, respectively. Bladder (yellow) and femoral heads (right femur: purple, left femur: pink) are also shown. Second row shows planning CT with EBRT dose distribution, taken just prior to EBRT delivery. Third row shows T2w MRI at the time of brachytherapy. Navy-Blue filled contour shows the 450 cGy brachytherapy isodose line. Cyan shows the acute fibrosis at 3 months following radiotherapy, which correlates with dose.

Figure 3: T2w and UTE MR images shown for a single representative subject (S4) post-EBRT. UTE TI=60ms subtraction images with acute fibrosis map in cyan and UTE Late Gadolinium Enhancement (13min post-injection) TI=200ms with chronic scar shown in pink. The white arrows in the UTE TI 60ms images indicate the pelvic lymph nodes. The white overlay is an anatomical map of pelvic lymph nodes (https://training.seer.cancer.gov/cervical-uterine/anatomy/lymph-nodes.html). Green arrow indicates the uterus and Yellow the cervix.

Figure 4: Brachytherapy dose distribution overlaid on CT (Row1) and MRI (Row2) T2w images acquired at the time of brachytherapy shown for a representative patient (S2). Cyan-filled contours indicate low fibrosis concentration and purple-filled contours indicate high fibrosis concentration based on the STIR-UTE TI=60ms image intensities, which were calibrated to the femur head cartilage signals (white arrows). The red contour identifies the planning treatment volume (PTV), which received the highest (45 Gy) EBRT dose.

Figure 5: Results of two patients (Left: S3, Right: S4) at two time points (Rows1-2: post-EBRT, Rows 3-4:3 months post-Brachy). Acute fibrosis (cyan) and chronic fibrosis (pink) maps are overlaid on T2w images acquired at respective time points. HDR isodose lines are shown in a color map, and red contour indicates the 45Gy EBRT isodose line (PTV). Patient S3, which displayed weak tumor response to RT, showed less conversion of acute fibrosis to chronic fibrosis at 3 months post-RT. Purple contour and white arrows (S3: 3mo T2) indicate residual disease based on segmented DWI (b=900 s/mm²).

Proc. Intl. Soc. Mag. Reson. Med. 30 (2022)

3409

DOI: https://doi.org/10.58530/2022/3409