PET/MRI 및 MR-IGRT를 위한 MRI 기반 합성 CT 생성의 타당성 연구

학위논문 (박사) -- 서울대학교 대학원 : 의과대학 의과학과, 2020. 8. 이재성.Over the past decade, the application of magnetic resonance imaging (MRI) in the field of diagnosis and treatment has increased. MRI provides higher soft-tissue contrast, especially in the brain, abdominal organ, and bone marrow without the expose of ionizing radiation. Hence, simultaneous positron emission tomography/MR (PET/MR) system and MR-image guided radiation therapy (MR-IGRT) system has recently been emerged and currently available for clinical study. One major issue in PET/MR system is attenuation correction from MRI scans for PET quantification and a similar need for the assignment of electron densities to MRI scans for dose calculation can be found in MR-IGRT system. Because the MR signals are related to the proton density and relaxation properties of tissue, not to electron density. To overcome this problem, the method called synthetic CT (sCT), a pseudo CT derived from MR images, has been proposed. In this thesis, studies on generating synthetic CT and investigating the feasibility of using a MR-based synthetic CT for diagnostic and radiotherapy application were presented. Firstly, MR image-based attenuation correction (MR-AC) method using level-set segmentation for brain PET/MRI was developed. To resolve conventional inaccuracy MR-AC problem, we proposed an improved ultrashort echo time MR-AC method that was based on a multiphase level-set algorithm with main magnetic field inhomogeneity correction. We also assessed the feasibility of level-set based MR-AC method, compared with CT-AC and MR-AC provided by the manufacturer of the PET/MRI scanner. Secondly, we proposed sCT generation from the low field MR images using 2D convolution neural network model for MR-IGRT system. This sCT images were compared to the deformed CT generated using the deformable registration being used in the current system. We assessed the feasibility of using sCT for radiation treatment planning from each of the patients with pelvic, thoraic and abdominal region through geometric and dosimetric evaluation.지난 10년간 진단 및 치료분야에서 자기공명영상(Magnetic resonance imaging; MRI) 의 적용이 증가하였다. MRI는 CT와 비교해 추가적인 전리방사선의 피폭없이 뇌, 복부 기관 및 골수 등에서 더 높은 연조직 대비를 제공한다. 따라서 MRI를 적용한 양전자방출단층촬영(Positron emission tomography; PET)/MR 시스템과 MR 영상 유도 방사선 치료 시스템(MR-image guided radiation therapy; MR-IGRT)이 진단 및 치료 방사선분야에 등장하여 임상에 사용되고 있다. PET/MR 시스템의 한 가지 주요 문제는 PET 정량화를 위한 MRI 스캔으로부터의 감쇠 보정이며, MR-IGRT 시스템에서 선량 계산을 위해 MR 영상에 전자 밀도를 할당하는 것과 비슷한 필요성을 찾을 수 있다. 이는 MR 신호가 전자 밀도가 아닌 조직의 양성자 밀도 및 T1, T2 이완 특성과 관련이 있기 때문이다. 이 문제를 극복하기 위해, MR 이미지로부터 유래된 가상의 CT인 합성 CT라 불리는 방법이 제안되었다. 본 학위논문에서는 합성 CT 생성 방법 및 진단 및 방사선 치료에 적용을 위한 MR 영상 기반 합성 CT 사용의 임상적 타당성을 조사하였다. 첫째로, 뇌 PET/MR를 위한 레벨셋 분할을 이용한 MR 이미지 기반 감쇠 보정 방법을 개발하였다. MR 이미지 기반 감쇠 보정의 부정확성은 정량화 오류와 뇌 PET/MRI 연구에서 병변의 잘못된 판독으로 이어진다. 이 문제를 해결하기 위해, 자기장 불균일 보정을 포함한 다상 레벨셋 알고리즘에 기초한 개선된 초단파 에코 시간 MR-AC 방법을 제안하였다. 또한 CT-AC 및 PET/MRI 스캐너 제조업체가 제공한 MR-AC와 비교하여 레벨셋 기반 MR-AC 방법의 임상적 사용가능성을 평가하였다. 둘째로, MR-IGRT 시스템을 위한 심층 컨볼루션 신경망 모델을 사용하여 저필드 MR 이미지에서 생성된 합성 CT 방법를 제안하였다. 이 합성 CT 이미지를 변형 정합을 사용하여 생성된 변형 CT와 비교 하였다. 또한 골반, 흉부 및 복부 환자에서의 기하학적, 선량적 분석을 통해 방사선 치료계획에서의 합성 CT를 사용가능성을 평가하였다.Chapter 1. Introduction 1 1.1. Background 1 1.1.1. The Integration of MRI into Other Medical Devices 1 1.1.2. Chanllenges in the MRI Integrated System 4 1.1.3. Synthetic CT Generation 5 1.2. Purpose of Research 6 Chapter 2. MRI-based Attenuation Correction for PET/MRI 8 2.1. Background 8 2.2. Materials and Methods 10 2.2.1. Brain PET Dataset 19 2.2.2. MR-Based Attenuation Map using Level-Set Algorithm 12 2.2.3. Image Processing and Reconstruction 18 2.3. Results 20 2.4. Discussion 28 Chapter 3. MRI-based synthetic CT generation for MR-IGRT 30 3.1. Background 30 3.2. Materials and Methods 32 3.2.1. MR-dCT Paired DataSet 32 3.2.2. Synthetic CT Generation using 2D CNN 36 3.2.3. Data Analysis 38 3.3. Results 41 3.3.1. Image Comparison 41 3.3.2. Geometric Analysis 49 3.3.3. Dosimetric Analysis 49 3.4. Discussion 56 Chapter 4. Conclusions 59 Bibliography 60 Abstract in Korean (국문 초록) 64Docto

Patient Risk-Minimizing Tube Current Modulation in X-Ray Computed Tomography

This dissertation proposes a patient-specific tube current modulation for computed tomography (CT) that minimizes the individual patient risk (riskTCM). Modern CT scanners use automatic exposure control (AEC) techniques including tube current modulation (TCM) to reduce the radiation dose delivered to the patient while maintaining image quality. Today's TCM implementations aim at minimizing the tube current-time (mAs) product as a surrogate for patient dose, which is why they are referred to as mAsTCM hereafter. However, the actual patient risk, e.g., in the form of risk measures such as the effective dose Deff representing the sensitivity of individual organs with respect to ionizing radiation, is not taken into account. In order to be able to optimize the effective dose Deff or another biologically meaningful measure, organ doses must be estimated before the actual CT scan in order to compute an optimized riskTCM curve. This can be achieved using a machine learning approach and based on these information, the new patient risk-minimizing TCM curve can be obtained. The proposed riskTCM algorithm was evaluated in a simulation study for circular scans and compared against the current gold standard method mAsTCM and to a constant tube current as well as an organ-specific tube current modulation technique. The results illustrate that all anatomical regions can benefit from riskTCM and a reduction of effective dose of up to 30% can be expected compared to mAsTCM. Furthermore, riskTCM was extended to a spiral trajectory that is commonly used in clinical routine and initial measurements with phantoms have been performed. The introduction of riskTCM into clinical practice would only require a software update since almost all CT systems are already capable of modulating the tube current

The potential role of MR-guided adaptive radiotherapy in pediatric oncology: Results from a SIOPE-COG survey

Background and purpose: Magnetic resonance guided radiotherapy (MRgRT) has been successfully implemented for several routine clinical applications in adult patients. The purpose of this study is to map the potential benefit of MRgRT on toxicity reduction and outcome in pediatric patients treated with curative intent for primary and metastatic sites. Materials and methods: Between May and August 2020, a survey was distributed among SIOPE- and COGaffiliated radiotherapy departments, treating at least 25 pediatrics patients annually and being (candidate) users of a MRgRT system. The survey consisted of a table with 45 rows (clinical scenarios for primary (n = 28) and metastatic (n = 17) tumors) and 7 columns (toxicity reduction, outcome improvement, PTV margin reduction, target volume daily adaptation, online re-planning, intrafraction motion compensation and on-board functional imaging) and the option to answer by ‘yes/no’ . Afterwards, the Dutch national radiotherapy cohort was used to estimate the percentage of pediatric treatments that may benefit from MRgRT. Results: The survey was completed by 12/17 (71% response rate) institutions meeting the survey inclusion criteria. Responders indicated an ‘expected benefit’ from MRgRT for toxicity/outcome in 7% (for thoracic lymphomas and abdominal rhabdomyosarcomas)/0% and 18% (for mediastinal lymph nodes, lymph nodes located in the liver/splenic hilum, and liver metastases)/0% of the considered scenarios for the primary and metastatic tumor sites, respectively, and a ‘possible benefit’ was estimated in 64%/46% and 47%/59% of the scenarios. When translating the survey outcome into a clinical perspective a toxicity/outcome benefit, either expected or possible, was anticipated for 55%/24% of primary sites and 62%/38% of the metastatic sites. Conclusion: Although the benefit of MRgRT in pediatric radiation oncology is estimated to be modest, the potential role for reducing toxicity and improving clinical outcomes warrants further investigation. This fits best within the context of prospective studies or registration trial

Improving Radiotherapy Targeting for Cancer Treatment Through Space and Time

Radiotherapy is a common medical treatment in which lethal doses of ionizing radiation are preferentially delivered to cancerous tumors. In external beam radiotherapy, radiation is delivered by a remote source which sits several feet from the patient\u27s surface. Although great effort is taken in properly aligning the target to the path of the radiation beam, positional uncertainties and other errors can compromise targeting accuracy. Such errors can lead to a failure in treating the target, and inflict significant toxicity to healthy tissues which are inadvertently exposed high radiation doses. Tracking the movement of targeted anatomy between and during treatment fractions provides valuable localization information that allows for the reduction of these positional uncertainties. Inter- and intra-fraction anatomical localization data not only allows for more accurate treatment setup, but also potentially allows for 1) retrospective treatment evaluation, 2) margin reduction and modification of the dose distribution to accommodate daily anatomical changes (called `adaptive radiotherapy\u27), and 3) targeting interventions during treatment (for example, suspending radiation delivery while the target it outside the path of the beam). The research presented here investigates the use of inter- and intra-fraction localization technologies to improve radiotherapy to targets through enhanced spatial and temporal accuracy. These technologies provide significant advancements in cancer treatment compared to standard clinical technologies. Furthermore, work is presented for the use of localization data acquired from these technologies in adaptive treatment planning, an investigational technique in which the distribution of planned dose is modified during the course of treatment based on biological and/or geometrical changes of the patient\u27s anatomy. The focus of this research is directed at abdominal sites, which has historically been central to the problem of motion management in radiation therapy

An investigation into the risk of population bias in deep learning autocontouring

Background and Purpose: To date, data used in the development of Deep Learning-based automatic contouring (DLC) algorithms have been largely sourced from single geographic populations. This study aimed to evaluate the risk of population-based bias by determining whether the performance of an autocontouring system is impacted by geographic population.Materials and methods: 80 Head Neck CT deidentified scans were collected from four clinics in Europe (n = 2) and Asia (n = 2). A single observer manually delineated 16 organs-at-risk in each. Subsequently, the data was contoured using a DLC solution, and trained using single institution (European) data. Autocontours were compared to manual delineations using quantitative measures. A Kruskal-Wallis test was used to test for any difference between populations. Clinical acceptability of automatic and manual contours to observers from each participating institution was assessed using a blinded subjective evaluation.Results: Seven organs showed a significant difference in volume between groups. Four organs showed statistical differences in quantitative similarity measures. The qualitative test showed greater variation in acceptance of contouring between observers than between data from different origins, with greater acceptance by the South Korean observers.Conclusion: Much of the statistical difference in quantitative performance could be explained by the difference in organ volume impacting the contour similarity measures and the small sample size. However, the qualitative assessment suggests that observer perception bias has a greater impact on the apparent clinical acceptability than quantitatively observed differences. This investigation of potential geographic bias should extend to more patients, populations, and anatomical regions in the future.</p

Impact of PET in the Radiation Therapy Planning for Pediatric Cancer

I Sverige drabbas omkring 300 barn av cancer varje år och majoriteten av dem är bara fyra-fem år gamla när de får sin diagnos. Omkring två tredjedelar av barncancerdiagnoserna utgörs av leukemier, lymfom och hjärntumörer, medan den sista tredjedelen är olika solida tumörformer som njurtumörer och nervvävnadstumörer i buken. Cancersjukvårdens utveckling under de senaste årtiondena har medfört en avsevärt förbättrad prognos för flertalet cancerdiagnoser. Ungefär tre fjärdedelar av barncancerpatienterna blir idag helt botade. De främsta behandlingsmetoderna är kirurgi, kemoterapi (cellgifter) och strålbehandling och de kan kombineras på olika sätt. I Sverige strålbehandlas ungefär hälften av alla cancerpatienter, och cirka en tredjedel av barncancerpatienterna, någon gång under sin sjukdomstid. Strålbehandlingen går ut på att en viss stråldos levereras till en specifik målvolym, som oftast utgörs av själva tumören inklusive marginaler. Strålningen som används har tillräckligt hög energi för att orsaka skador på kroppens celler, till exempel genom att jonisera atomer och bryta molekylbindningar. Detta kan bland annat påverka DNA-molekylen i cellkärnan. Tyvärr är det ofrånkomligt att även friska celler bestrålas, och givetvis kan strålningen orsaka bestående påverkan även inuti dessa. Skadorna motarbetas dock av de reparationsprocesser som ständigt pågår i kroppen och lyckligtvis nog sker reparationen oftast betydligt mer effektivt i de friska cellerna än i tumörceller. För att undvika skador i frisk vävnad är det dock viktigt att inte bestråla en onödigt stor volym. Att skona den friska vävnaden men samtidigt leverera en tillräckligt hög dos till tumören är en av de största utmaningarna inom modern strålbehandling. Detta är ännu viktigare för unga patienter, eftersom barn är extra känsliga för strålning och riskerna för negativa bieffekter är större än hos vuxna. Dessutom har barn fler levnadsår framför sig än vuxna patienter, vilket innebär fler år för komplikationer att hinna utvecklas och ge besvär. Inom extern strålbehandling har det under de senaste årtiondena utvecklats nya behandlingstekniker. I kombination med CT-baserad (Computed Tomography, datortomografi) dosplanering har dessa förbättrat möjligheterna att mer exakt leverera stråldos till den önskade målvolymen. Denna mer konforma dosfördelning gör det möjligt att öka den absorberade dosen till tumören utan att öka stråldosen till omgivande frisk vävnad. Den gör det också möjligt att minska behandlingsmarginalerna, men detta innebär i sin tur att det blir ännu viktigare säkerställa vilken volym som behöver behandlas. Behovet av att komplettera traditionella undersökningsmetoder som CT med andra informationskällor har ökat. PET (positronemissionstomografi) är en nuklearmedicinsk bildtagningsmodalitet som blivit ett allt viktigare komplement till CT vid diagnostisering och behandlingsplanering av cancersjukdomar. Precis som vid de flesta nuklearmedicinska undersökningar injiceras ett radioaktivt preparat i patienten. Aktiviteten fördelar sig i patientens kropp och kan avbildas med hjälp av olika detektorer. Genom att fästa den radioaktiva isotopen till en molekyl med känt biologiskt rörelsemönster kan man till viss del styra var i kroppen aktiviteten ska hamna. Vid PET-scanning används ofta den radioaktiva isotopen fluor-18 som fästs vid en glukosliknande molekyl. Glukos (druvsocker) är en viktig energikälla och tas upp av celler i proportion till deras ämnesomsättning. Detta innebär att radioaktiviteten ackumuleras i celler med hög metabolism – något som ofta är fallet med maligna tumörceller. PET-bilden kan därmed vara till stor hjälp vid inritningen av målvolymer. Syftet med denna studie är att studera om – och i så fall hur – målvolymerna ändras av att den kliniska informationen kompletteras med PET-bilder. Strålbehandlingsplaner har gjorts till båda varianter och för ett flertal strålbehandlingstekniker. Målet är att med hjälp av teoretiska modeller baserade på publicerade data försöka upptäcka och kvantifiera skillnader mellan planerna med och utan PET, med avseende på risken för komplikationer. Resultaten visar att användningen av PET kan förändra målvolymerna till såväl storlek som form. Trots detta var det inte möjligt att påvisa någon signifikant förändring av riskerna för komplikationer av själva strålbehandlingen.Purpose: The purpose of this study was to evaluate the impact of including PET (Positron Emission Tomography) in the process of pediatric radiation therapy planning. The aim was to study the effect on target volumes and how this in turn affects the resulting treatment plans. This study also aims to compare the estimated risks of various long-term complications and how the use of PET influences these risks. Methods: Eleven pediatric sarcoma, NSCLC (non-small-cell lung cancer) and nasopharyngeal cancer patients, treated at Rigshospitalet in 2005-2011, were included in this study. The target volumes (GTV:s and CTV:s) were delineated by senior clinicians specialized in nuclear medicine, diagnostic radiology and radiation oncology. The delineation was performed without and subsequently with access to the PET scan information, on separate CT-sets. A margin of 6 mm was added to each CTV to render the PTV. Treatment plans were generated for three different photon therapy modalities and intensity-modulated proton therapy. Dose-effects models based on published studies were derived to evaluate and compare the risks of complications. Moreover, a rough estimation of the effective dose from the PET/CT scan and the associated risk was made. Results: The target volumes were evaluated with respect to volume size as well as shape. For the patients in this study, there was no significant change of the size of the target volumes: the average CTV size was 257 cm3 (range: 71.10-462.40 cm3, median 259.60 cm3) and 254 cm3 (range: 63.43-497.30 cm3, median 211.90 cm3) without and with PET respectively. Using PET did in some cases alter the shape of the treatment volumes, resulting in a mean Dice index of 0.91 (range: 0.86-0.95). The radiation therapy plans based on PET data were not significantly different from the noPET-plans, in neither the risk of normal tissue complications, nor the risk of secondary cancers. The impact of PET did not differ between the four treatment modalities. Conclusions: The main conclusion from this study is that while including PET in the radiation therapy treatment planning process of pediatric cancer patients may change the shape and size of the target volume, it does not significantly impact the risks attributable to the radiation therapy, neither of normal tissue complications nor secondary cancers. The risk of radiation-induced complications from the PET/CT scan is very small. The target volume may be decreased by including PET, when areas dubious on the CT are FDG-negative. This gives the potential to reduce the irradiated normal tissue volume. The PET-based target volume may be expanded for FDG-positive areas that are undistinguishable on the CT-images. This will likely decrease the risk of leaving malignant tissue untreated. The results suggest that there will be no significant differences between radiation therapy plans made with or without PET-data. The plans appear to be of comparable quality (provided that the therapeutic efficacy is maintained) and the risk of long-term complications is not changed. A vast amount of published results from more than a decade of research and clinical experience, indicate the usefulness and diagnostic value of including PET-data into the care of cancer patients – adults as well as children. Taking these factors into consideration, along with the very low risks of radiation-induced side effects from the PET/CT scan itself, the conclusion is that PET should be used as a complementary tool in target volume delineation for radiation therapy planning of pediatric patients