Optimizing SABR delivery for synchronous multiple lung tumors using volumetric-modulated arc therapy.

BACKGROUND: Volumetric-modulated arc therapy (VMAT) delivery for stereotactic ablative radiotherapy (SABR) of multiple lung tumors allows for faster treatments. We report on clinical outcomes and describe a general approach for treatment planning. MATERIAL AND METHODS: Patients undergoing multi iso-center VMAT-based SABR for ≥2 lung lesions between 2009 and 2014 were identified from the VU University Medical Center and London Health Sciences Centre. Patients were eligible if the start date of the SABR treatment for the different lesions was within a time range of 30 days. SABR was delivered using separate iso-centers for lesions at a substantial distance from each other. Tumors were either treated with a single fraction of 34 Gy, or using three risk-adapted dose-fractionation schemes, namely three fractions of 18 Gy, five fractions of 11 Gy, or eight fractions of 7.5 Gy, depending on the tumor size and the location. Multivariable analysis was performed to assess factors predictive of clinical outcomes. RESULTS: Of 84 patients (188 lesions) identified, 46% were treated for multiple metastases and 54% for multiple primary NSCLC. About 97% were treated for two or three lesions, and 56% had bilateral disease. After a median follow-up of 28 months, median overall survival (OS) for primary tumors was 27.6 months, and not reached for metastatic lesions (p = .028). Grade ≥3 toxicity was observed in 2% of patients. Multivariable analysis showed that grade 2 or higher radiation pneumonitis (n = 9) was best predicted by a total lung V35Gy of ≥6.5% (in 2Gy/fraction equivalent) (p = .007). CONCLUSION: Severe toxicity was uncommon following SABR using VMAT for up to three lung tumors. Further investigations of planning parameters are needed in patients presenting with more lesions.

Accuracy of deformable image registration-based intra-fraction motion management in Magnetic Resonance-guided radiotherapy.

Background and Purpose: Intra-fraction motion management is key in Stereotactic Ablative Radiotherapy (SABR) gated delivery. This study assessed the accuracy of automatic tumor segmentation in the delivery of MR-guided radiotherapy (MRgRT) by comparing it to manual delineations performed by experienced observers. Materials and Methods: Twenty patients previously treated with MR-guided SABR for thoracic and abdominal tumors were included. Five observers with at least two years of experience in MRgRT manually delineated the gross tumor volume (GTV) for 20 patients on 240 frames of a cine MRI on a sagittal plane. Deformable Image Registration (DIR) based GTV contours were propagated using four different algorithms from a reference frame to subsequent frames.Geometrical analysis based on the Dice Similarity Coefficient (DSC), centroid distance and Hausdorff Distance (HDD) were performed to assess the inter-observer variability and the accuracy of automatic segmentation. A Confidence Value (CV) metric for the reliability of the tumor auto-contouring was also calculated. Results: Inter-observer delineation variability resulted in mean DSC of 0.89, HDD of 5.8 mm and centroid distance of 1.7 mm. Tumor auto-contouring by the four DIR algorithms resulted in an excellent agreement with the manual delineations by the experienced observers. Mean DSC for each algorithm across all patients was greater than 0.90, whereas the HDD and centroid distances were below 4.0 mm and 1.5 mm, respectively. The CV showed a strong correlation with the DSC. Conclusions: DIR-based auto-contouring in MRgRT exhibited a high level of agreement with the manual contouring performed by experts, allowing accurate gated delivery.

Magnetic resonance imaging-guided radiotherapy for intermediate- and high-risk prostate cancer: Trade-off between planning target volume margin and online plan adaption.

Magnetic resonance-guided radiotherapy with daily plan adaptation for intermediate- and high-risk prostate cancer is time and labor intensive. Fifty adapted plans with 3 mm planning target volume (PTV)-margin were compared with non-adapted plans using 3 or 5 mm margins. Adequate (V95% ≥ 95%) prostate coverage was achieved in 49 fractions with 5 mm PTV without plan adaptation, however, coverage of the seminal vesicles (SV) was insufficient in 15 of 50 fractions. There was no insufficient coverage for prostate and SV using plan adaptation with 3 mm. Hence, daily adaptation is recommended to obtain adequate SV-coverage when using 3 mm PTV.

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.

Magnetic Resonance-guided Stereotactic Radiotherapy for Localized Prostate Cancer: Final Results on Patient-reported Outcomes of a Prospective Phase 2 Study.

BACKGROUND: The recent introduction of magnetic resonance-guided radiation therapy (MRgRT) has allowed improved treatment planning and delivery of stereotactic body radiotherapy (SBRT) in prostate cancer (PC). The health-related quality of life (HRQoL) outcomes using this novel approach are important in shared decision making for patients. OBJECTIVE: To report HRQoL using both patient- and clinician-reported outcomes at 1 yr following stereotactic MRgRT for patients with localized PC. DESIGN, SETTING, AND PARTICIPANTS: A prospective phase 2 trial included 101 patients with localized PC. INTERVENTION: All patients received 36.25Gy in five fractions of MRgRT delivered within 2 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was prospectively assessed at baseline, at the last fraction, at 6 wk, and at 3, 6, 9, and 12 mo after treatment, by patient-reported outcome measures using European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-PR25 questionnaires, and International Prostate Symptom Score. At the same time points, clinicians reported on symptomatic adverse events (AEs). Effect sizes for changes in HRQoL were calculated with repeated measures analysis of variance. RESULTS AND LIMITATIONS: Availability of HRQoL data exceeded 95% at all study time points. From both questionnaires and the recorded AEs, the largest treatment effects on urinary and bowel symptoms were recorded in the first 6 wk of follow-up. Thereafter, all symptoms decreased and returned to baseline values at 12 mo. No grade ≥3 toxicity was reported. No patient reported any relevant limitation due to urinary symptoms, and only 2.2% of patients reported a relevant impact on daily activities due to bowel problems at 1 yr. The majority of patients had intermediate- or high-risk PC for which androgen deprivation therapy (83.2%) was prescribed, thereby precluding study of MRgRT on sexual function. Longer follow-up is awaited in order to evaluate the oncological outcome. CONCLUSIONS: Delivery of MRgRT for SBRT resulted in low toxicity at 1 yr. PATIENT SUMMARY: All patients completed magnetic resonance-guided radiation therapy, which was well tolerated with only transient early urinary and bowel symptoms, which resolved 1 yr after treatment, as confirmed by patient-reported outcome measures.

The Role of Daily Adaptive Stereotactic MR-Guided Radiotherapy for Renal Cell Cancer.

Novel magnetic-resonance-guided radiotherapy (MRgRT) permits real-time soft-tissue visualization, respiratory-gated delivery with minimal safety margins, and time-consuming daily plan re-optimisation. We report on early clinical outcomes of MRgRT and routine plan re-optimization for large primary renal cell cancer (RCC). Thirty-six patients were treated with MRgRT in 40 Gy/5 fractions. Prior to each fraction, re-contouring of tumor and normal organs on a pretreatment MR-scan allowed daily plan re-optimization. Treatment-induced toxicity and radiological responses were scored, which was followed by an offline analysis to evaluate the need for such daily re-optimization in 180 fractions. Mean age and tumor diameter were 78.1 years and 5.6 cm, respectively. All patients completed MRgRT with an average fraction duration of 45 min. Local control (LC) and overall survival rates at one year were 95.2% and 91.2%. No grade ≥3 toxicity was reported. Plans without re-optimization met institutional radiotherapy constraints in 83.9% of 180 fractions. Thus, daily plan re-optimization was required for only a minority of patients, who can be identified upfront by a higher volume of normal organs receiving 25 Gy in baseline plans. In conclusion, stereotactic MRgRT for large primary RCC showed low toxicity and high LC, while daily plan re-optimization was required only in a minority of patients.

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.

A Prospective Single-Arm Phase 2 Study of Stereotactic Magnetic Resonance Guided Adaptive Radiation Therapy for Prostate Cancer: Early Toxicity Results.

PURPOSE: Use of stereotactic body radiation therapy (SBRT) is increasing in patients with localized prostate cancer, but concerns about early and late gastrointestinal (GI) and genitourinary (GU) toxicity exist after moderately or extremely hypofractionated radiation therapy schemes. Magnetic resonance guided radiation therapy (MRgRT) was clinically introduced in 2014. MrgRT allows for SBRT delivery with smaller uncertainty margins and permits daily adaptive planning. A phase 2 study in patients with localized prostate cancer was performed to study early GI and GU toxicity after SBRT using MRgRT. METHODS AND MATERIALS: One hundred one patients with clinical stage T1-3bN0M0 prostate cancer were enrolled in this prospective phase 2 study. All but 4 patients had intermediate- or high-risk prostate cancer, and 82.2% received adjuvant hormonal treatment. MRgRT was delivered in 5 fractions of 7.25 Gy to the target volume using daily plan adaptation with simultaneous relative sparing of the urethra to a dose of 6.5 Gy per fraction. Early toxicity was studied using both clinician- (Common Terminology Criteria for Adverse Events and Radiation Therapy Oncology Group) and patient-reported outcome measurements (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30, Quality of Life Questionnaire PR25, and International Prostate Symptom Scoring). RESULTS: The maximum cumulative grade ≥2 early GU and GI toxicity measured by any symptom at any study time point was 23.8% and 5.0%, respectively. No early grade 3 GI toxicity was observed. Early grade 3 GU toxicity was 0% and 5.9% according to the Common Terminology Criteria for Adverse Events and Radiation Therapy Oncology Group and scoring systems, respectively, as a result of different grading of radiation cystitis. The low incidence of early GI toxicity was confirmed by patient-reported outcome data. GU grade ≥2 toxicity peaked to 19.8% at the end of MRgRT, followed by a return to the baseline average score at 3-month follow-up. CONCLUSIONS: This prospective study of MRgRT in patients with localized prostate cancer observed a low incidence of early GI and GU toxicity, both in clinician- and patient-reported outcome measurements.

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

In this case presentation, we describe the challenges of performing magnetic resonance-guided radiation therapy (MRgRT) with plan adaptation in a patient with advanced endometriosis, in whom several prior therapeutic attempts were unsuccessful and extensive pelvic irradiation was regarded as being too toxic. Treatment was delivered in two sessions, first for the seemingly only active right ovary, and at a later stage for the left ovary. Some logistical problems were encountered during the preparation of the first treatment, which were subsequently optimized for the second treatment by using transvaginal ultrasound to determine the optimum time point for simulation and delivery. Using breath-hold gated delivery and plan adaptation, radiation dose to the bowel could be minimized, resulting in good tolerance of treatment. Because of the need to simulate and deliver in a brief optimal time span for visibility of the follicles in the ovaries, a single fraction dose of 8 Gy was used in our patient. Hormonal outcome after her second treatment is still pending. In conclusion, MRgRT with plan adaptation is feasible for the occasional patient with refractory endometriosis. Simulation and delivery needs to be synchronized with the menstrual cycle, ensuring that the Graafian follicles allow the ovaries to be visible on magnetic resonance imaging (MRI). Because the ovaries are only visible on T2-weighted MRI for a very brief period of time, we suggest that it is preferable to use single fraction radiotherapy with a brief interval between simulation imaging and delivery.

Combined Inter- and Intrafractional Plan Adaptation Using Fraction Partitioning in Magnetic Resonance-guided Radiotherapy Delivery.

Magnetic resonance-guided radiation therapy (MRgRT) not only allows for superior soft-tissue setup and online MR-guidance during delivery but also for inter-fractional plan re-optimization or adaptation. This plan adaptation involves repeat MR imaging, organs at risk (OARs) re-contouring, plan prediction (i.e., recalculating the baseline plan on the anatomy of that moment), plan re-optimization, and plan quality assurance. In contrast, intrafractional plan adaptation cannot be simply performed by pausing delivery at any given moment, adjusting contours, and re-optimization because of the complex and composite nature of deformable dose accumulation. To overcome this limitation, we applied a practical workaround by partitioning treatment fractions, each with half the original fraction dose. In between successive deliveries, the patient remained in the treatment position and all steps of the initial plan adaptation were repeated. Thus, this second re-optimization served as an intrafractional plan adaptation at 50% of the total delivery. The practical feasibility of this partitioning approach was evaluated in a patient treated with MRgRT for locally advanced pancreatic cancer (LAPC). MRgRT was delivered in 40Gy in 10 fractions, with two fractions scheduled successively on each treatment day. The contoured gross tumor volume (GTV) was expanded by 3 mm, excluding parts of the OARs within this expansion to derive the planning target volume for daily re-optimization (PTVOPT). The baseline GTVV95% achieved in this patient was 80.0% to adhere to the high-dose constraints for the duodenum, stomach, and bowel (V33 Gy <1 cc and V36 Gy <0.1 cc). Treatment was performed on the MRIdian (ViewRay Inc, Mountain View, USA) using video-assisted breath-hold in shallow inspiration. The dual plan adaptation resulted, for each partitioned fraction, in the generation of PlanPREDICTED1, PlanRE-OPTIMIZED1 (inter-fractional adaptation), PlanPREDICTED2, and PlanRE-OPTIMIZED2 (intrafractional adaptation). An offline analysis was performed to evaluate the benefit of inter-fractional versus intrafractional plan adaptation with respect to GTV coverage and high-dose OARs sparing for all five partitioned fractions. Interfractional changes in adjacent OARs were substantially larger than intrafractional changes. Mean GTV V95% was 76.8 ± 1.8% (PlanPREDICTED1), 83.4 ± 5.7% (PlanRE-OPTIMIZED1), 82.5 ± 4.3% (PlanPREDICTED2),and 84.4 ± 4.4% (PlanRE-OPTIMIZED2). Both plan re-optimizations appeared important for correcting the inappropriately high duodenal V33 Gy values of 3.6 cc (PlanPREDICTED1) and 3.9 cc (PlanPREDICTED2) to 0.2 cc for both re-optimizations. To a smaller extent, this improvement was also observed for V25 Gy values. For the stomach, bowel, and all other OARs, high and intermediate doses were well below preset constraints, even without re-optimization. The mean delivery time of each daily treatment was 90 minutes. This study presents the clinical application of combined inter-fractional and intrafractional plan adaptation during MRgRT for LAPC using fraction partitioning with successive re-optimization. Whereas, in this study, interfractional plan adaptation appeared to benefit both GTV coverage and OARs sparing, intrafractional adaptation was particularly useful for high-dose OARs sparing. Although all necessary steps lead to a prolonged treatment duration, this may be applied in selected cases where high doses to adjacent OARs are regarded as critical.

Patient-reported Outcome Measurements on the Tolerance of Magnetic Resonance Imaging-guided Radiation Therapy.

Purpose Magnetic resonance imaging-guided radiation therapy (MRgRT) requires patient positioning within the MR bore and prolonged MR imaging during delivery, both of which are new in radiation oncology. Patient tolerance of MRgRT was prospectively evaluated using patient-reported outcome questionnaires (PRO-Q). Methods Our MRgRT procedure involves daily high-resolution MR scanning, limited re-contouring, daily plan re-optimization, quality assurance (QA), and gated delivery. Patients with claustrophobia are excluded. Mean fraction duration was 45 and 60 minutes for stereotactic treatments during free-breathing and breath-hold, respectively. Patient-controlled video-feedback was used for breath-hold delivery. PRO-Qs collected in the first 150 patients treated included questions on MR-related complaints and also evaluated aspects of active participation. Results Almost one-third of patients (29%) scored at least one PRO-Q item on MR-related complaints as 'moderate' or 'very much', with noise, feeling cold, and paresthesia being the most frequently scored in this way. Considerable anxiety was reported by 5%, but no medication was required for this in any patient. Patient participation in video feedback for breath-hold delivery was appreciated by the majority of patients, all of whom completed the procedure. Only 5% of patients considered treatment duration to be unacceptably long. Conclusion Despite the lengthy MRgRT procedure, outcomes of PRO-Q indicate that it was well-tolerated by patients.

Imaging texture analysis for automated prediction of lung cancer recurrence after stereotactic radiotherapy.

Benign radiation-induced lung injury (RILI) is not uncommon following stereotactic ablative radiotherapy (SABR) for lung cancer and can be difficult to differentiate from tumor recurrence on follow-up imaging. We previously showed the ability of computed tomography (CT) texture analysis to predict recurrence. The aim of this study was to evaluate and compare the accuracy of recurrence prediction using manual region-of-interest segmentation to that of a semiautomatic approach. We analyzed 22 patients treated for 24 lesions (11 recurrences, 13 RILI). Consolidative and ground-glass opacity (GGO) regions were manually delineated. The longest axial diameter of the consolidative region on each post-SABR CT image was measured. This line segment is routinely obtained as part of the clinical imaging workflow and was used as input to automatically delineate the consolidative region and subsequently derive a periconsolidative region to sample GGO tissue. Texture features were calculated, and at two to five months post-SABR, the entropy texture measure within the semiautomatic segmentations showed prediction accuracies [areas under the receiver operating characteristic curve (AUC): 0.70 to 0.73] similar to those of manual GGO segmentations (AUC: 0.64). After integration into the clinical workflow, this decision support system has the potential to support earlier salvage for patients with recurrence and fewer investigations of benign RILI.