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

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

An end-to-end test for MR-guided online adaptive radiotherapy

In the evolving field of adaptive MR guided radiotherapy, the need for dedicated procedures for acceptance and quality assurance is increasing. Research has been devoted to MR compatible dosimeters and phantoms, but to date no end-to-end test has been presented that covers an MRgRT workflow. Such an end-to-end test should comprise each step of the workflow and include all associated uncertainties. The purpose of this study was to investigate the usability of an anthropomorphic deformable and multimodal pelvis (ADAM-pelvis) phantom in combination with film dosimetry for end-to-end testing of an MRgRT adaptive workflow. The ADAM-pelvis phantom included surrogates for muscle tissue, adipose and bone, as well as deformable silicone organs mimicking a prostate patient. At the interfaces of the critical structures (bladder and rectum), small pieces of GafChromic EBT3 films were placed to measure delivered dose. Pre-treatment MR imaging of the phantom was used to delineate the prostate, rectum and bladder and to generate a treatment plan to deliver 2 Gy to the prostate. Electron density (ED) map from CT imaging was used for dose calculation after deformable image registration (DIR) to the pre-treatment MR scan. At each fraction, bladder- and rectum filling was varied and a new adapted plan was generated. Dose calculation was performed using both a DIR-based ED map and a CT-based ED map after acquisition of a new CT scan of the phantom at each fraction. All dose calculations were performed taking into account the magnetic field. A good agreement between measured and calculated dose was found using both, the CT-derived and the DIR-based ED map (2.0% and 2.8% dose difference, respectively). The gamma index pass-rate (3%/2 mm) varied from 96.4% to 100%.The ADAM-pelvis phantom was suitable for end-to-end testing in MR-guided radiotherapy and a very good agreement with the calculated dose was achieved

Dose accumulation for personalized stereotactic MR-guided adaptive radiation therapy in prostate cancer

Background and purpose: Adaptive MR-guided radiotherapy (MRgRT) is an innovative approach for delivering stereotactic body radiotherapy (SBRT) in prostate cancer (PC). Despite the increased clinical use of SBRT for PC, there is limited data on the relation between the actual delivered dose and toxicity. We aimed to identify dose parameters based on the total accumulated delivered bladder dose (DOSEACCTX). Furthermore, for future personalization, we studied whether prospective accumulation of the first 3 of 5 fractions (DOSEACC3FR) could be used as a representative of DOSEACCTX. Materials and methods: We deployed a recently validated deformable image registration-based dose accumulation strategy to reconstruct DOSEACCTX and DOSEACC3FR in 101 PC patients treated with stereotactic MRgRT. IPSS scores at baseline, end of MRgRT, at 6 and 12 weeks after treatment were analyzed to identify a clinically relevant increase of acute urinary symptoms. A receiver operator characteristic curve analysis was used to investigate the correlation of an increase in IPSS and bladder DOSEACCTX (range V5–V36.25 Gy, D1cc, D5cc) and DOSEACC3FR (range V6–V21.8 Gy, D1cc, D5cc) parameters. Results: A clinically relevant increase in IPSS in the three months following MRgRT was observed in 25 patients. The V20Gy-32Gy from DOSEACCTX and V15Gy-18Gy from DOSEACC3FR showed good correlation with IPSS increase with area under the curve (AUC) values ranging from 0.71 to 0.75. In contrast, baseline dosimetry showed a poor correlation with AUC values between 0.53 and 0.62. Conclusion: DOSEACCTX was superior to baseline dosimetry in predicting acute urinary symptoms. Because DOSEACC3FR also showed good correlation, this can potentially be used to optimize MRgRT for the remaining fractions

Clinical implementation of magnetic resonance imaging guided adaptive radiotherapy for localized prostate cancer

BACKGROUND AND PURPOSE Magnetic resonance-guided radiation therapy (MRgRT) has recently become available in clinical practice and is expected to expand significantly in coming years. MRgRT offers marker-less continuous imaging during treatment delivery, use of small clinical target volume (CTV) to planning target volume (PTV) margins, and finally the option to perform daily plan re-optimization. MATERIALS AND METHODS A total of 140 patients (700 fractions) have been treated with MRgRT and online plan adaptation for localized prostate cancer since early 2016. Clinical workflow for MRgRT of prostate cancer consisted of patient selection, simulation on both MR- and computed tomography (CT) scan, inverse intensity-modulated radiotherapy (IMRT) treatment planning and daily plan re-optimization prior to treatment delivery with partial organs at risk (OAR) recontouring within the first 2 cm outside the PTV. For each adapted plan online patient-specific quality assurance (QA) was performed by means of a secondary Monte Carlo 3D dose calculation and gamma analysis comparison. Patient experiences with MRgRT were assessed using a patient-reported outcome questionnaire (PRO-Q) after the last fraction. RESULTS In 97% of fractions, MRgRT was delivered using the online adapted plan. Intrafractional prostate drifts necessitated 2D-corrections during treatment in approximately 20% of fractions. The average duration of an uneventful fraction of MRgRT was 45 min. PRO-Q’s (N = 89) showed that MRgRT was generally well tolerated, with disturbing noise sensations being most commonly reported. CONCLUSIONS MRgRT with daily online plan adaptation constitutes an innovative approach for delivering SBRT for prostate cancer and appears to be feasible, although necessitating extended timeslots and logistical challenges

The effect of induction chemotherapy on tumor volume and organ-at-risk doses in patients with locally advanced oropharyngeal cancer

Background and purpose: To retrospectively report changes in gross tumor volume (GTV) and organ-at-risk (OAR) doses after induction chemotherapy (IC) in oropharyngeal cancer using different contouring strategies. Materials and methods: GTV and OARs were delineated on pre- and post-IC planning CT. Two post-IC GTV contours were made: (I) a 'consensus set' using published guidelines (GTV(consensus)). and (2) 'visible set', delineating only visible post-IC GTV (GTV(visible)). Pre-IC interactively optimized volumetric modulated arc therapy plans were generated. The pre-IC planning constraints served as the starting point for both post-IC plans. Results reflect pooled data from all 10 patients. Results: Mean reduction in volume post-IC was 24% and 47% for consensus and visible primary tumor and 57% and 60% for consensus and visible nodes. Compared to pre-IC plans, average mean OAR dose for post-IC GTV(consensus) plans was significantly lower for CL parotid. For GTV(visible) plans both parotids, upper/lower larynx, inferior pharyngeal constrictor and cricopharyngeal muscles were significantly lower. However reductions compared with post-IC GTV(consensus) plans were modest (1.6/1.5/1.2/3.7/5.9/2.6 Gy, respectively). Conclusion: IC in patients with oropharyngeal carcinoma results in substantial reductions in GTVs. If post-IC GTVs are used, which is contrary to current consensus, statistically significant but relatively small OAR dose reductions are observed. (C) 2013 Elsevier Ireland Ltd. All rights reserved

Identification of patients with locally advanced pancreatic cancer benefitting from plan adaptation in MR-guided radiation therapy

Background and purpose: MR-guided radiation therapy (MRgRT) with daily plan adaptation is a novel but time- and resource-intensive treatment for locally advanced pancreatic cancer (LAPC). We analyzed the benefit in target coverage and organ-at-risk (OAR) sparing of daily plan adaptation in 36 consecutive LAPC patients treated with MRgRT to 40 Gy in 5 fractions. Materials and methods: Adaptive planning was assessed for 180 fractions by comparing non-adapted plans with re-optimized plans using (a) GTV coverage and OAR high-doses, and (b) compliance with institutional objectives for GTV coverage and high-dose OAR constraints. Using these criteria, plan adaptation for each fraction was characterized as “not needed” “beneficial” or “no benefit”. Decision-tree analysis was performed to identify subgroups most likely or not to benefit from routine plan adaptation. Results: The percentage of plans fulfilling institutional constraints increased from 43.9% (non-adapted plans) to 83.3% after online plan adaptation, with significant improvements in GTV coverage and lower V33Gy OAR doses. Adaptive re-optimization was found to be “not needed” in 80 fractions (44.4%), “beneficial” in 95 fractions (52.8%) and of “no benefit” in 5 fractions (2.8%). Decision-tree analysis identified a grouping based on distance from tumor to OAR of ≤3 mm and GTV size, respectively, to be the major determinants for the benefit of daily plan adaptation. Conclusion: MRgRT with daily plan adaptation for LAPC was of benefit in approximately half of fractions, improving target coverage and OAR sparing. Plan adaptation appeared to be relevant mainly in cases where the GTV to adjacent OAR distance was ≤3 mm

Same-day consultation, simulation and lung Stereotactic Ablative Radiotherapy delivery on a Magnetic Resonance-linac

Background and Purpose: Magnetic resonance-guided radiotherapy (MRgRT) with real-time intra-fraction tumor motion monitoring allows for high precision Stereotactic Ablative Radiotherapy (SABR). This study aimed to investigate the clinical feasibility, patient satisfaction and delivery accuracy of single-fraction MR-guided SABR in a single day (one-stop-shop, OSS). Methods and Materials: Ten patients with small lung tumors eligible for single fraction treatments were included. The OSS procedure consisted of consultation, treatment simulation, treatment planning and delivery. Following SABR delivery, patients completed a reported experience measure (PREM) questionnaire. Prescribed doses ranged 28–34 Gy. Median GTV was 2.2 cm3 (range 1.3–22.9 cm3). A gating boundary of 3 mm, and PTV margin of 5 mm around the GTV, were used with auto-beam delivery control. Accuracy of SABR delivery was studied by analyzing delivered MR-cines reconstructed from machine log files. Results: All 10 patients completed the OSS procedure in a single day, and all reported satisfaction with the process. Median time for the treatment planning step and the whole procedure were 2.8 h and 6.6 h, respectively. With optimization of the procedure, treatment could be completed in half a day. During beam-on, the 3 mm tracking boundary encompassed between 78.0 and 100 % of the GTV across all patients, with corresponding PTV values being 94.4–100 % (5th-95th percentiles). On average, system-latency for triggering a beam-off event comprised 5.3 % of the delivery time. Latency reduced GTV coverage by an average of −0.3 %. Duty-cycles during treatment delivery ranged from 26.1 to 64.7 %. Conclusions: An OSS procedure with MR-guided SABR for lung cancer led to good patient satisfaction. Gated treatment delivery was highly accurate with little impact of system-latency