ADAPTIVE MR-GUIDED RADIOTHERAPY: FROM CONCEPT TO ROUTINE PRACTICE

Radiotherapy is an established curative treatment for cancer and is also widely used in the treatment of metastatic disease. Magnetic resonance guided radiotherapy (MRgRT) represents a major treatment advance as it permits precise soft tissue setup and the continuous visualization of tumors and surrounding organs, thereby improving the safety and effectiveness of radiotherapy delivery. MRgRT was first introduced clinically in 2014, and in 2016, the Amsterdam UMC became the first Dutch adopters, focusing on treating patients using stereotactic ablative radiotherapy (SABR). The work performed in this thesis describes a number of approaches developed in order to ensure a practical and feasible workflow for MRgRT delivery of SABR using daily on-couch adaptive treatment plan delivery whenever possible. A key development was the strategy for plan adaptation using only a single treatment optimization step that only requires clinicians to review and adjust organ contours located within 2-3 cm from the target. This novel and fast approach resulted in treatment plans meeting all clinical constraints, and contributed to the feasibility of using daily adaptive MRgRT, as plan adaptation added only about 15 minutes to the total workflow. Use of this strategy has led to more than 1200 patients undergoing 6000 treatment fractions to tumor in the prostate, pancreas, high-risk lung cancer, renal- and adrenal lesions, and liver metastases. Almost all fractions have been delivered using the adapted plan. The delivery of daily adapted MRgRT requires time slots of approximately 45 to 60 minutes for SABR delivery. To reduce treatment times further, it is essential to identify patients groups that are less likely to benefit from having a new daily radiotherapy plan, and our studies identified patients with abdominal tumors who could be treated faster without plan adaptation. This will permit a more efficient use of resources. Organs in the body can move during treatment, leading to a need for intrafractional adapted radiotherapy plans. To approach this problem, we used fraction partitioning with successive re-optimization, and showed that plan adaptation benefits both tumor coverage and healthy organ sparing. Similarly, plan adaptation during treatment was also shown to be useful in some instances, although it can prolong the treatment duration to 90 minutes. The continuous visualization of anatomical changes during MRgRT allows for a more accurate reconstruction of delivered doses to tumors and organs. Our study of accumulated radiation doses revealed that the accumulated bladder dose in 100 patients with prostate cancer better predicted acute radiation-related urinary toxicity, than was possible using the baseline radiotherapy plans. This finding opens the door for personalized radiation delivery approaches using prospective dose accumulation for each subsequent fraction. In summary, the work performed for this thesis has allowed for fast and accurate delivery of MRgRT, and it has identified a number of areas for further improvements in treatment efficiency

Pitfalls of Ovarian Ablative Magnetic Resonance-guided Radiation Therapy for Refractory Endometriosis.

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Role of Daily Plan Adaptation in MR-Guided Stereotactic Ablative Radiation Therapy for Adrenal Metastases

AbstractPurpose To study inter-fractional organ changes during MR-guided stereotactic ablative radiotherapy (SABR) for adrenal metastases and to evaluate the dosimetric advantages of online plan adaptation. Methods and Materials Seventeen patients underwent a total of 84 fractions of video-assisted, respiration-gated MR-guided adaptive radiotherapy to deliver either 50 Gy (5 fractions), 60 Gy (8 fractions) or 24 Gy (3 fractions). An MR scan was repeated prior to each fraction, followed by rigid co-registration to the GTV on the pre-treatment MR scan. Contour deformation, PTV (GTV+3mm) expansion and online plan re-optimization were then performed. Re-optimized plans were compared to baseline treatment plans recalculated on the anatomy-of-the-day (‘predicted plans'). Inter-fractional changes in OARs were quantified according to OAR volume changes within a 3 cm distance from PTV surface, centre of mass (COM) displacements and the Dice Similarity Coefficient (DSC). Plan quality evaluation was based on target coverage (GTV and PTV), and also high dose sparing of all OARs (V36Gy, V33Gy and V25Gy). Results Substantial COM displacements were observed for stomach, bowel and duodenum of 17, 27 and 36 mm, respectively. Maximum volume changes for the stomach, bowel and duodenum within 3 cm of PTV were 23.8, 20.5 and 20.9 cc, respectively. DSC values for OARs ranged from 0.0 to 0.9 for all fractions. Baseline plans recalculated on anatomy-of-the-day revealed underdosage of target volumes, and variable OAR sparing, leading to a failure to meet institutional constraints in a third of fractions. Online re-optimization improved target coverage in 63% of fractions, and reduced the number of fractions not meeting the V95% objective for GTV and PTV. Re-optimized plans exhibited significantly better sparing of OAR. Conclusions Significant inter-fractional changes in OARs positions were observed despite breath-hold SABR delivery under MR-guidance. Online re-optimization of treatment plans led to significant improvements in target coverage and OAR sparing

Fast and robust online adaptive planning in stereotactic MR-guided adaptive radiation therapy (SMART) for pancreatic cancer

Background and purpose To implement a robust and fast stereotactic MR-guided adaptive radiation therapy (SMART) online strategy in locally advanced pancreatic cancer (LAPC). Material and methods SMART strategy for plan adaptation was implemented with the MRIdian system (ViewRay Inc.). At each fraction, OAR (re-)contouring is done within a distance of 3 cm from the PTV surface. Online plan re-optimization is based on robust prediction of OAR dose and optimization objectives, obtained by building an artificial neural network (ANN). Proposed limited re-contouring strategy for plan adaptation (SMART3CM) is evaluated by comparing 50 previously delivered fractions against a standard (re-)planning method using full-scale OAR (re-)contouring (FULLOAR). Plan quality was assessed using PTV coverage (V95%, Dmean, D1cc) and institutional OAR constraints (e.g. V33Gy). Results SMART3CMrequired a significant lower number of optimizations than FULLOAR (4 vs 18 on average) to generate a plan meeting all objectives and institutional OAR constraints. PTV coverage with both strategies was identical (mean V95%= 89%). Adaptive plans with SMART3CMexhibited significant lower intermediate and high doses to all OARs than FULLOAR, which also failed in 36% of the cases to adhere to the V33Gydose constraint. Conclusions SMART3CMapproach for LAPC allows good OAR sparing and adequate target coverage while requiring only limited online (re-)contouring from clinicians