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Background While patients with diffuse low-grade glioma (LGG) often survive for years, there is a risk of tumor progression which may impact patients’ long-term health-related quality of life (HRQOL) and neurocognitive functioning (NCF). We present a follow-up of LGG patients and their informal caregivers (T3) who took part in our previous HRQOL investigations (T1, M = 7 and T2 M = 13 years after diagnosis). Methods Participants completed HRQOL (short form-36 health survey [SF-36]; EORTC-BN20), fatigue (Checklist Individual Strength [CIS]), and depression (Center for Epidemiological Studies-Depression [CES-D]) questionnaires and underwent NCF assessments. T3 scores were compared with matched controls. Changes over time (T1–T2–T3) on group and participant level were assessed. Where available, histology of the initial tumor was revised and immunohistochemical staining for IDH1 R132H mutant protein was performed. Results Thirty patients and nineteen caregivers participated. Of N = 11 with tissue available, 3 patients had confirmed diffuse LGG. At T3, patients (M = 26 years after diagnosis) had HRQOL and NCF similar to, or better than controls, yet 23.3% and 53.3% scored above the cut-off for depression (≥16 CES-D) and fatigue (≥35 CIS), respectively. Caregivers’ HRQOL was similar to controls but reported high rates of fatigue (63.2%). Over time, patients’ mental health improved (P < .05). Minimal detectable change in HRQOL over time was observed in individual patients (30% improvement; 23.3% decline; 20% both improvement and decline) with 23.3% remaining stable. NCF remained stable or improved in 82.8% of patients. Conclusions While HRQOL and NCF do not appear greatly impacted during long-term survivorship in LGG, depressive symptoms and fatigue are persistent.

Introduction: Stereotactic ablative radiotherapy (SABR) can achieve good local control for metastatic adrenal lesions. Magnetic resonance (MR)-guidance with daily on-table plan adaptation can augment the delivery of SABR with greater dose certainty. The goal of this study was to quantify the potential clinical benefit MR-guided daily-adaptive adrenal SABR using the normal tissue complication probability (NTCP) framework. Methods: Patients treated with adrenal MR-guided SABR at a single institution were retrospectively reviewed. Lyman-Kutcher-Burman NTCP models were used to calculate the NTCP of upper abdominal organs-at-risk (OARs) at simulation and both before and after daily on-table plan adaptation. Differences in OAR NTCPs were assessed using signed-rank tests. Potential predictors of the benefits of adaptation were assessed by linear regression. Results: Fifty-two adrenal MR-guided SABR courses were analyzed. The baseline simulation plan underestimated the absolute stomach NTCP by 10.0% on average (95% confidence interval: 4.7–15.2%, p < 0.001). Daily on-table adaptation lowered absolute NTCP by 8.7% (4.2–13.2%, p < 0.001). The most significant predictor of the benefits of adaptation was lesion laterality (p = 0.018), with left-sided lesions benefitting more (13.3% [6.3–20.4%], p < 0.001) than right-sided lesions (2.1% [−1.6–5.7%], p = 0.25). Sensitivity analyses did not change the statistical significance of the findings. Conclusion: NTCP analysis revealed that patients with left adrenal tumors were more likely to benefit from MR-guided daily on-table adaptive SABR using current dose/fractionation regimens due to reductions in predicted gastric toxicity. Right-sided adrenal lesions may be considered for dose escalation due to low predicted NTCP.

Background: Stereotactic radiotherapy (SRT) is an attractive treatment option for patients with brain metastases (BM), sparing healthy brain tissue and likely controlling local tumors. Most previous studies have focused on radiological response or survival. Our randomized trial (NCT02353000) investigated whether quality of life (QoL) is better preserved using SRT than whole-brain radiotherapy (WBRT) for patients with multiple BM. Recently, we published our trial’s primary endpoints. The current report discusses the study’s secondary endpoints. Methods: Patients with 4 to 10 BM were randomly assigned to a standard-arm WBRT (20 Gy in 5 fractions) or SRT group (1 fraction of 15–24 Gy or 3 fractions of 8 Gy). QoL endpoints—such as EQ5D domains post-treatment, the Barthel index, the European Organisation for Research and Treatment of Cancer (EORTC) questionnaires, and the neurocognitive Hopkins Verbal Learning Test—were evaluated. Results: Due to poor accrual resulting from patients’ and referrers’ preference for SRT, this study closed prematurely. The other endpoints’ results were published recently. Twenty patients were available for analysis (n=10 vs. n=10 for the two groups, respectively). Significant differences were observed 3 months post-treatment for the mobility (P=0.041), self-care (P=0.028), and alopecia (P=0.014) EQ5D domains, favoring SRT. This self-care score also persisted compared to the baseline (P=0.025). Multiple EORTC categories reflected significant differences, favoring SRT—particularly physical functioning and social functioning. Conclusions: For patients with multiple BM, SRT alone led to persistently higher QoL than treatment with WBRT. Trial Registration: ClinicalTrials.gov, NCT02353000.

Background and purpose: Effective combination treatments with fractionated radiotherapy rely on a proper understanding of the dynamic responses that occur during treatment. We explored the effect of clinical fractionated radiotherapy on the development and timing of radioresistance in tumor cells. Methods and materials: Different colon (HT29/HCT116/COLO320/SW480/RKO) and high-grade astrocytoma (D384/U-251MG) cancer cell lines were treated for 6 weeks with daily fractions of 2 Gy, 5 days per week. Clonogenic survival was determined throughout the treatment period. In addition, the radiosensitivity of irradiated and non-irradiated was compared. Finally, the effect of different dose fractions on the development of radioresistance was determined. Results: All cell lines developed radioresistance within 2–3 weeks during fractionated radiotherapy. This was characterized by the occurrence of a steady state phase of clonogenic survival. In U-251MG cells this was accompanied by increased cell senescence and stemness. After recovering from six weeks of treatment, the radiosensitivity of fractionally irradiated and non-irradiated cells was similar. Including transient radioresistance, described as (α/β)−( d +1), as a factor in the classic LQ model resulted in a perfect fit with the experimental data observed during fractionated radiotherapy. This was confirmed when different dose fractions were applied. Conclusions: Fractionated irradiation of cancer cells in vitro following clinical radiation schedules induces a reversible radioresistance response. This adaptive response can be included in the LQ model as a function of the dose fraction and the alpha/beta-ratio of a given cell line. These findings warrant further investigation of the mechanisms and clinical relevance of adaptive radioresistance.

BACKGROUND AND PURPOSE: We studied the benefits of using stereotactic MR-guided adaptive radiation therapy (SMART) for delivery of SABR in peripherally located lung tumors.METHODS AND MATERIALS: Twenty-three patients (25 peripheral lung tumors) underwent SMART in 3-8 fractions on an MR Linac or Cobalt-60 system. Before each fraction, a breath-hold MR scan was acquired, followed by on-table plan adaptation based on the anatomy-of-the-day. Breath-hold gated delivery was performed under continuous MR-guidance using an in-room monitor. Benefits of on-table adaptation were studied by comparing 112 «predicted» plans, which are the baseline plans recalculated on the anatomy-of-the-day, with the on-table reoptimized plans.RESULTS: The full SMART procedure took a median of 48 and 62 minutes on the MR Linac and Cobalt-60 system, respectively. Median SMART-PTVs were 9.5 cm3 (range, 3.1-55.6). In 14 patients who had undergone a free-breathing 4DCT, SMART-PTVs measured 53.7% (range, 31.9-75.0) of PTVs that would have been generated using a motion-encompassing internal target volume approach. On-table adaptation improved prescription dose coverage of the PTV from a median of 92.1% in predicted plans, to 95.0% in reoptimized ones, thereby increasing the proportion of fractions delivering ≥100 Gy (BED10Gy) to 95% of PTV, from 90.2% to 100.0%.CONCLUSION: Delivery of gated breath-hold SABR using MR-guidance resulted in significantly smaller target volumes than would have been the case with an ITV-based approach. Although on-table adaptation ensured delivery of ablative doses in all fractions, the dosimetric benefits were modest, suggesting that daily online plan adaptation may not benefit most patients with peripheral lung tumors.

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.

Purpose: As patients with centrally located lung tumors are at increased risk of toxicity with stereotactic ablative radiation therapy (SABR), we performed stereotactic magnetic resonance (MR)-guided adaptive radiation therapy (SMART) for such patients. We retrospectively analyzed the benefits of daily on-table plan adaptation. Methods and Materials: Twenty-five patients with central lung tumors underwent a total of 182 fractions of video-assisted, respiration-gated SMART on the MRIdian (ViewRay, Inc). Risk-adapted fractionation was used to deliver 60 Gy in 8 fractions (n = 20) or 55 Gy in 5 fractions (n = 5). For each fraction, daily MR-guided setup and on-table plan reoptimization, based on planning target volume (PTV) coverage and organ-at-risk (OAR) constraints, was performed. Gated breath-hold delivery was performed under continuous MR guidance. Benefits of daily plan reoptimization were studied by comparing 168 “predicted” plans, which are the calculated baseline plans on the anatomy of the day, with the reoptimized treatment plans. Results: The reoptimized plan was chosen for treatment in 92% of fractions. On-table plan adaptation improved PTV coverage in 61% of fractions by achieving superior coverage by the prescription dose (V 100% ) and a higher median dose (D 50% ). Mean increase in PTV V 100% was 4.6% (P

Background Adaptive magnetic resonance imaging‐guided radiation therapy (MRgRT) can escalate dose to tumors while minimizing dose to normal tissue. We evaluated outcomes of inoperable pancreatic cancer patients treated using MRgRT with and without dose escalation. Methods We reviewed 44 patients with inoperable pancreatic cancer treated with MRgRT. Treatments included conventional fractionation, hypofractionation, and stereotactic body radiation therapy. Patients were stratified into high‐dose (biologically effective dose [BED10] >70) and standard‐dose groups (BED10 ≤70). Overall survival (OS), freedom from local failure (FFLF) and freedom from distant failure (FFDF) were evaluated using Kaplan‐Meier method. Cox regression was performed to identify predictors of OS. Acute gastrointestinal (GI) toxicity was assessed for 6 weeks after completion of RT. Results Median follow‐up was 17 months. High‐dose patients (n = 24, 55%) had statistically significant improvement in 2‐year OS (49% vs 30%, P = 0.03) and trended towards significance for 2‐year FFLF (77% vs 57%, P = 0.15) compared to standard‐dose patients (n = 20, 45%). FFDF at 18 months in high‐dose vs standard‐dose groups was 24% vs 48%, respectively (P = 0.92). High‐dose radiation (HR: 0.44; 95% confidence interval [CI]: 0.21‐0.94; P = 0.03) and duration of induction chemotherapy (HR: 0.84; 95% CI: 0.72‐0.98; P = 0.03) were significantly correlated with OS on univariate analysis but neither factor was independently predictive on multivariate analysis. Grade 3+ GI toxicity occurred in three patients in the standard‐dose group and did not occur in the high‐dose group. Conclusions Patients treated with dose‐escalated MRgRT demonstrated improved OS. Prospective evaluation of high‐dose RT regimens with standardized treatment parameters in inoperable pancreatic cancer patients is warranted.

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.

Online magnetic resonance-guided radiotherapy (oMRgRT) represents one of the most innovative applications of current image-guided radiation therapy (IGRT). The revolutionary concept of oMRgRT systems is the ability to acquire MR images for adaptive treatment planning and also online imaging during treatment delivery. The daily adaptive planning strategies allow to improve targeting accuracy while avoiding critical structures. This ESTRO-ACROP recommendation aims to provide an overview of available systems and guidance for best practice in the implementation phase of hybrid MR-linac systems. Unlike the implementation of other radiotherapy techniques, oMRgRT adds the MR environment to the daily practice of radiotherapy, which might be a new experience for many centers. New issues and challenges that need to be thoroughly explored before starting clinical treatments will be highlighted.

Background The clinical value of whole brain radiotherapy (WBRT) for brain metastases (BM) is a matter of debate due to the significant side effects involved. Stereotactic radiosurgery (SRS) is an attractive alternative treatment option that may avoid these side effects and improve local tumor control. We initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS compared with WBRT in patients with multiple brain metastases. Methods Patients with 4–10 BM were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). The primary endpoint was the difference in quality of life (QOL) at 3 months post-treatment. Results The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions were 6 (range: 4–9) and the median total treatment volume was 13.0 cc3 (range: 1.8–25.9 cc3). QOL at 3 months decreased in the SRS group by 0.1 (SD = 0.2), compared to 0.2 (SD = 0.2) in the WBRT group (P = .23). The actuarial 1-year survival rates were 57% (SRS) and 31% (WBRT) (P = .52). The actuarial 1-year brain salvage-free survival rates were 50% (SRS) and 78% (WBRT) (P = .22). Conclusion In patients with 4–10 BM, SRS alone resulted in 1-year survival for 57% of patients while maintaining quality of life. Due to the premature closure of the trial, no statistically significant differences could be determined.

The guideline on brain metastasis from the Netherlands Society of Neurology has been updated. Important changes have been made, particularly with regard to treatment of brain metastases. Treatment of patients with brain metastases is complex and requires a multidisciplinary approach to formulate an optimal, individualized treatment plan. Neurosurgical resection may also be considered in patients with multiple brain metastases and one dominant, symptomatic lesion, if the patient is in good clinical condition. Stereotactic radiosurgery is a treatment option for patients with a maximum of 10 brain metastases, depending on the size and number of metastases. The indication for whole brain radiotherapy is relatively limited. Doctors should be cautious with whole brain radiotherapy in patients with a Karnofsky Performance Status70. In patients with small, asymptomatic brain metastases, targeted therapy or immune therapy may be considered without locoregional therapy.

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 &ge, 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.

Background Surgical resection and irradiation of diffuse glioma are guided by standard MRI: T2/fluid attenuated inversion recovery (FLAIR)–weighted MRI for non-enhancing and T1-weighted gadolinium-enhanced (T1G) MRI for enhancing gliomas. Amino acid PET has been suggested as the new standard. Imaging combinations may improve standard MRI and amino acid PET. The aim of the study was to determine the accuracy of imaging combinations to detect glioma infiltration. Methods We included 20 consecutive adults with newly diagnosed non-enhancing glioma (7 diffuse astrocytomas, isocitrate dehydrogenase [IDH] mutant; 1 oligodendroglioma, IDH mutant and 1p/19q codeleted; 1 glioblastoma IDH wildtype) or enhancing glioma (glioblastoma, 9 IDH wildtype and 2 IDH mutant). Standardized preoperative imaging (T1-, T2-, FLAIR-weighted, and T1G MRI, perfusion and diffusion MRI, MR spectroscopy and O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]FET) PET) was co-localized with multiregion stereotactic biopsies preceding resection. Tumor presence in the biopsies was assessed by 2 neuropathologists. Diagnostic accuracy was determined using receiver operating characteristic analysis. Results A total of 174 biopsies were obtained (63 from 9 non-enhancing and 111 from 11 enhancing gliomas), of which 129 contained tumor (50 from non-enhancing and 79 from enhancing gliomas). In enhancing gliomas, the combination of apparent diffusion coefficient (ADC) with [18F]FET PET (area under the curve [AUC], 95% CI: 0.89, 0.79‒0.99) detected tumor better than T1G MRI (0.56, 0.39‒0.72; P < 0.001) and [18F]FET PET (0.76, 0.66‒0.86; P = 0.001). In non-enhancing gliomas, no imaging combination detected tumor significantly better than standard MRI. FLAIR-weighted MRI had an AUC of 0.81 (0.65–0.98) compared with 0.69 (0.56–0.81; P = 0.019) for [18F]FET PET. Conclusion Combining ADC and [18F]FET PET detects glioma infiltration better than standard MRI and [18F]FET PET in enhancing gliomas, potentially enabling better guidance of local therapy.

Background: Since publication of the QUARTZ trial, the clinical value of whole brain radiotherapy (WBRT) for brain metastases is a matter of debate due to significant side effects. In order to avoid these side effects and to improve local tumor control, stereotactic radiosurgery (SRS) is an attractive treatment option. We have initiated a randomized trial (NCT02353000) to investigate whether quality of life is better preserved after SRS alone than after WBRT in patients with newly diagnosed multiple brain metastases. Methods: Patients with 4 up to 10 brain metastases (BM) were randomized between the standard arm WBRT (total dose 20 Gy in 5 fractions) or SRS (single fraction or 3 fractions). Primary endpoint was difference in quality of life (QOL) at three months after radiotherapy compared to baseline (EQ5D5L EUROQOL score). Findings: The study was prematurely closed due to poor accrual. A total of 29 patients (13%) were randomized between July 2016 and May 2018, of which 15 patients have been treated with SRS and 14 patients with WBRT. The median number of lesions per patient was 6 (range, 4-9) and the median total treatment volume was 13.0 cc 3 (range, 1.8-25.9 cc 3 ). QOL at three months decreased in the SRS group with 0.1 (SD=0.2), compared to 0.2 (SD=0.2) in the WBRT group (p=0.23).The actuarial one year survival was 57% (SRS) and 31% (WBRT) (p=0.52). The actuarial one year brain salvage free survival was 50% (SRS) and 78% (WBRT) (p=0.22). Interpretation: In patients with 4 up to 10 BM, SRS alone resulted in one-year survival in 57% of patients while maintaining quality of life. Due to premature closure of the trial, no statistical significant differences could be determined between SRS alone and WBRT in the investigated endpoints. Trial Registration: NCT02353000 Funding Statement: Varian Medical Systems, the Dutch technology Foundation STW, and Kankeronderzoekfonds Limburg. Declaration of Interests: No competing interests to declare. Ethics Approval Statement: All patients willing to participate gave written informed consent. The study protocol was approved by the medical ethical committee of the Maastricht University Medical Center, The Netherlands.

PurposeTo 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 MaterialsSeventeen 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).ResultsSubstantial 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.ConclusionsSignificant 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.

BACKGROUND Delay in cancer care may adversely affect emotional distress, treatment outcome and survival. Optimal timings in multidisciplinary glioblastoma care are a matter of debate and clear national guidelines only exist for time to neurosurgery. We evaluated the between-hospital variation in timings to neurosurgery and adjuvant radiotherapy and chemotherapy in newly diagnosed glioblastoma patients in the Netherlands. MATERIAL AND METHODS Data were obtained from the nation-wide Dutch Brain Tumor Registry between 2014 and 2018. All adult patients with glioblastoma were included, covering all 18 neurosurgical hospitals, 28 radiotherapy hospitals, and 33 oncology hospitals. Long time-to-surgery (TTS) was defined as >3 weeks from the date of first brain tumor diagnosis to surgery, long time-to-radiotherapy (TTR) as either >4 or >6 weeks after surgery, and long time-to-chemotherapy (TTC) as either >4 or >6 weeks after completion of radiotherapy. Between-hospital variation in standardized rate of long timings was analyzed in funnel plots after case-mix correction. RESULTS A total of 4203 patients were included. Median TTS was 20 days and 52.4% of patients underwent surgery within 3 weeks. Median TTR was 20 days and 24.6% of patients started radiotherapy within 4 weeks and 84.2% within 6 weeks after surgery. Median TTC was 28 days and 62.6% of patients received chemotherapy within 4 weeks and 91.8% within 6 weeks after radiotherapy. After case-mix correction, three (16.7%) neurosurgical hospitals had significantly more patients with longer than expected TTS. Three (10.7%) and one (3.6%) radiotherapy hospitals had significantly more patients with longer than expected TTR for >4 and >6 weeks, respectively. In seven (21.2%) chemotherapy hospitals, significantly less patients with TTC >4 weeks were observed than expected. In four (12.1%) chemotherapy hospitals, significantly more patients with TTC >4 weeks were observed than expected. CONCLUSION Between-hospital variation in timings to multidisciplinary treatment was observed in glioblastoma care in the Netherlands. A substantial percentage of patients experienced timings longer than anticipated.

BACKGROUND Over the past years, increasing worldwide attention towards centralization of complex cancer care has been pursued as higher volume centers have shown improved outcomes. Changes in distribution of care and the impact on travel distance in glioblastoma patients have not been determined yet. In this study, we determine trends in distribution of glioblastoma care in the Netherlands over the last three decades and assess whether the observed trends affected travel distance for individual patients. MATERIAL AND METHODS Data were obtained from the Dutch Brain Tumor Registry from 1989 to 2018. All glioblastoma patients (≥18 years) were included for analysis. Patients, neurosurgical centers and radiotherapy centers were geocoded. Data were analyzed in six time intervals of 5 years. High volume hospitals were defined as >50 cases per year. Travel distance was examined in two categories, ≤60km and >60km respectively. Trend analyses for proportions were used to analyze hospital volume changes and travel distances. RESULTS A total of 16.477 glioblastoma patients were registered, with an annual increase from 203 patients in 1989 to 917 patients in 2018. Neurosurgical centers increased from 16 to 17 and for radiotherapy from 19 to 22 centers between 1989–1993 and 2014–2018. Mean neurosurgical- and radiotherapy center volumes increased from 12 to 39 (P=0.025) and 7 to 27 (P=0.025) patients per hospital per year from 1989–1993 to 2014–2018. High volume neurosurgical centers were observed since 2004, and an increased number of patients were treated in these centers, 27.8%, 52.6% and 64.1% in the time periods 2004–2008, 2009–2013, and 2014–2018 (P60km to the neurosurgical center reduced from 15.8% to 13.2% (P=0.033). Travel distance >60km to the radiotherapy center did not reduce significantly (10.4% to 8.8%, P=0.601). CONCLUSION An increasing number of glioblastoma patients were differentially treated in high volume neurosurgery and radiotherapy centers. The observation that this did not translate into increased travel distances, indicates accessible specialized Neuro-Oncology care for glioblastoma patients in The Netherlands.

Introduction: Commonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations.Methods: 495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in four Dutch radiation oncology centers were identified and divided in a training cohort (n = 214, patients treated in one hospital) and an external validation cohort n = 281, patients treated in three other hospitals). Using the training cohort, nomograms were developed for prediction of early death (12 months) with prognostic factors for survival. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival. The accuracy of the nomograms was also tested in the external validation cohort.Results: Prognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival. In the external validation cohort, the nomogram predicted early death statistically significantly better (p Conclusion: The nomograms predicted early death and long-term survival more accurately than commonly used prognostic scores after SRS for a limited number of BMs of NSCLC. Moreover these nomograms enable individualized probability assessment and are easy into use in routine clinical practice. (C) 2017 Elsevier B.V. All rights reserved.

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.

Magnetic Resonance-guided radiotherapy (MRgRT) marks the beginning of a new era. MR is a versatile and suitable imaging modality for radiotherapy, as it enables direct visualization of the tumor and the surrounding organs at risk. Moreover, MRgRT provides real-time imaging to characterize and eventually track anatomical motion. Nevertheless, the successful translation of new technologies into clinical practice remains challenging. To date, the initial availability of next-generation hybrid MR-linac (MRL) systems is still limited and therefore, the focus of the present preview was on the initial applicability in current clinical practice and on future perspectives of this new technology for different treatment sites. MRgRT can be considered a groundbreaking new technology that is capable of creating new perspectives towards an individualized, patient-oriented planning and treatment approach, especially due to the ability to use daily online adaptation strategies. Furthermore, MRL systems overcome the limitations of conventional image-guided radiotherapy, especially in soft tissue, where target and organs at risk need accurate definition. Nevertheless, some concerns remain regarding the additional time needed to re-optimize dose distributions online, the reliability of the gating and tracking procedures and the interpretation of functional MR imaging markers and their potential changes during the course of treatment. Due to its continuous technological improvement and rapid clinical large-scale application in several anatomical settings, further studies may confirm the potential disruptive role of MRgRT in the evolving oncological environment.

Purpose Magnetic resonance (MR)-guided SABR was performed for patients with lung tumors in whom treatment delivery was challenging owing to tumor location, motion, or pulmonary comorbidity. Because stereotactic MR-guided adaptive radiation therapy (SMART) is a novel approach, we studied clinical outcomes in these high-risk lung tumors. Methods and Materials Fifty consecutive patients (54 lung tumors) underwent SMART between 2016 and 2018 for either a primary lung cancer (29 patients) or for lung metastases (21 patients). Eligible patients had risk factors that could predispose them to toxicity, including a central tumor location (n = 30), previous thoracic radiation therapy (n = 17), and interstitial lung disease (n = 7). A daily 17-second breath-hold MR scan was acquired in treatment position, and on-table plan adaptation was performed using the anatomy of the day. Gated SABR was delivered during repeated breath-holds under continuous MR guidance. Results All but 1 patient completed the planned SMART schedule. With daily plan adaptation, a biologically effective dose ≥100 Gy to 95% of the planning target volume was delivered in 50 tumors (93%). Median follow-up was 21.7 months (95% confidence interval, 19.9-28.1). Local control and overall and disease-free survival rates at 12 months were 95.6%, 88.0%, and 63.6%, respectively. Local failures developed in 4 patients: in 2 after reirradiation for a recurrent lung cancer and in 2 patients with a colorectal metastasis. Overall rates of any grade ≥2 and ≥3 toxicity were 30% and 8%, respectively. Commonest toxicities were grade ≥2 radiation pneumonitis (12%) and chest wall pain (8%). No grade 4 or 5 toxicities were observed. Conclusions Use of MR-guided SABR resulted in low rates of high-grade toxicity and encouraging early local control in a cohort of high-risk lung tumors. Additional studies are needed to identify patients who are most likely to benefit from the SMART approach.

OBJECTIVES: Stage I non-small cell lung cancer (NSCLC) can be treated with either Stereotactic Body Radiotherapy (SBRT) or Video Assisted Thoracic Surgery (VATS) resection. To support decision making, not only the impact on survival needs to be taken into account, but also on quality of life, costs and cost-effectiveness. Therefore, we performed a cost-effectiveness analysis comparing SBRT to VATS resection with respect to quality adjusted life years (QALY) lived and costs in operable stage I NSCLC.MATERIALS AND METHODS: Patient level and aggregate data from eight Dutch databases were used to estimate costs, health utilities, recurrence free and overall survival. Propensity score matching was used to minimize selection bias in these studies. A microsimulation model predicting lifetime outcomes after treatment in stage I NSCLC patients was used for the cost-effectiveness analysis. Model outcomes for the two treatments were overall survival, QALYs, and total costs. We used a Dutch health care perspective with 1.5 % discounting for health effects, and 4 % discounting for costs, using 2018 cost data. The impact of model parameter uncertainty was assessed with deterministic and probabilistic sensitivity analyses.RESULTS: Patients receiving either VATS resection or SBRT were estimated to live 5.81 and 5.86 discounted QALYs, respectively. Average discounted lifetime costs in the VATS group were €29,269 versus €21,175 for SBRT. Difference in 90-day excess mortality between SBRT and VATS resection was the main driver for the difference in QALYs. SBRT was dominant in at least 74 % of the probabilistic simulations.CONCLUSION: Using a microsimulation model to combine available evidence on survival, costs, and health utilities in a cost-effectiveness analysis for stage I NSCLC led to the conclusion that SBRT dominates VATS resection in the majority of simulations.

Purpose: To evaluate the performance of the hippocampal normal tissue complication model that relates dose to the bilateral hippocampus to memory impairment at 18 months post-treatment in a population of low-grade glioma (LGG) patients.Methods: LGG patients treated within the radiotherapy-only arm of the EORTC 22033-26033 trial were analyzed. Hippocampal dose parameters were calculated from the original radiotherapy plans. Difference in Rey Verbal Auditory Learning test delayed recall (AVLT-DR) performance pre-and 18 (+/- 4) months post-treatment was compared to reference data from the Maastricht Aging study. The NTCP model published by Gondi et al. was applied to the dosimetric data and model predictions were compared to actual neurocognitive outcome.Results: A total of 29 patients met inclusion criteria. Mean dose in EQD2Gy to the bilateral hippocampus was 39.8Gy (95% CI 34.3-44.4Gy), the median dose to 40% of the bilateral hippocampus was 47.2 EQD2Gy. The model predicted a risk of memory impairment exceeding 99% in 22 patients. However, only seven patients were found to have a significant decline in AVLT-dr score.Conclusions: In this dataset of only LGG patients treated with radiotherapy the hippocampus NTCP model did not perform as expected to predict cognitive decline based on dose to 40% of the bilateral hippocampus. Caution should be taken when extrapolating this model outside of the range of dose-volume parameters in which it was developed.

Background and purpose This work evaluates the accuracy of deformable dose accumulation for organs at risk (OAR) in MR-guided prostate SBRT using an anthropomorphic deformable phantom. Materials and methods Six MR-guided prostate SBRT treatment courses were simulated using volumetric OAR (bladder and rectum) information derived from actual patient data. Deformed OAR contours, geometrical landmarks and GafChromic EBT3 film strips (1.25 × 2.0 cm2) placed at the surface of the OARs were used to validate DIR-based dose accumulation in MRgRT. Two DIR methods were applied: an intensity-based deformation (IB-D) applied to the whole image, and a contour-based deformation (CB-D), resulting in a separate deformation and dose accumulation for each OAR. Dosimetric accuracy was evaluated by quantifying the dose differences, and performing a gamma-index analysis between measured and DIR-derived accumulated dose for both OARs. Geometrical accuracy was assessed by measuring the Dice similarity coefficient (DSC), Hausdorff distance (HDD) and residual distance error (RDE) for all markers at each fraction. Results CB-D resulted in an average dose deviation from film measurements for rectum and bladder surfaces of 0.6% and 0.3%, respectively. IB-D led to worse results resulting in an overall average dose accumulation inaccuracy of 7.2% and 2.5% for rectum and bladder. CB-D also showed a higher geometrical accuracy than IB-D with significantly higher DSC values and lower RDE and HDD deviations. Conclusion Empirical validation of dose accumulation in MR-guided SBRT for prostate cancer obtained a good agreement with reference film measurements when using a contour-based DIR approach.

Highlights • The use of MRgRT in clinical practice requires thorough preparation. • MRgRT combining with daily plan adaptation indicates adjusting existing workflows. • Clinical implementation of adaptive MRgRT requires a multidisciplinary approach. • Role and responsibilities of RTT will expand with growing clinical experience., The latest development in radiation oncology departments towards high precision and adaptive radiation therapy is the clinical introduction of magnetic resonance image guided radiation therapy (MRgRT). Early 2016, patient treatment using MRgRT was started at Amsterdam UMC, location VU University Medical Center. Introducing this novel technique in clinical practice requires thorough preparation with regard to important topics, such as MR-safety and training, equipping the treatment vault and console room, development of MRgRT workflow and logistical issues. Certainly when MRgRT is combined with daily plan adaptation, this indicates adjusting existing workflows and protocols. The MRgRT workflow requires a multidisciplinary process, and while each discipline has had its own tasks and responsibilities, with growing clinical experience there has been a shift towards RTT responsibilities. In this overview we discuss preclinical training and preparation for the implementation of (adaptive) MRgRT, with a particular focus on the perspective of RTTs. Although the reviewed logistics are partly the result of the decision to perform daily plan re-optimization, our experience can be extrapolated to implementation of alternative approaches for MRgRT.

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. Keywords: Prostate cancer, MR-guided Radiotherapy (MRgRT), Stereotactic body radiotherapy (SBRT), On-table adaptation, Workflow

Purpose/objective(s) Radionecrosis (RN) has previously been correlated with radiosurgery (RS) dose, lesion volume, and the volume of the brain receiving specific doses, i.e. V 10–14Gy . A knowledge-based individualized estimation of the optimum RS dose has been derived based on lesional volume and brain toxicity parameters. Methods and materials A prediction model for brain toxicity parameters and estimation of the optimum RS dose was derived using 30 historical linac-based dynamic conformal arc RS plans for single brain metastases (BM) (0.2–20.3cc) with risk-adapted dose prescription ranging from 15 to 24Gy. Derivation of the model followed a three-step process: (1) Derivation of formulas for the prediction of brain toxicity parameters V 10–18Gy ; (2) Establishing the relationship of the coefficients used for the prediction of V 12Gy with prescription dose; (3) Derivation of the optimum prescription dose for a given maximum V 12Gy as a function of a given lesion volume. Model validation was performed on 65 new patients with 138 lesions (44 with multiple BM) treated with non-coplanar volumetric modulated stereotactic arc treatment (VMAT). Results A linear dependence with the PTV size was found for all investigated brain toxicity parameters ( V 10–18Gy ). Individualized RS prescription doses can be calculated for any given PTV size based on a linear relationship between V 12Gy and PTV size, according to the formula PD = \[ V 12 Gy + 0.96 + \( 1.44 × PTV \) \] / \[ 0.12 + \( 0.12 × PTV \) \] . A very good correlation ( R 2 =0.991) was found between the predicted V 12Gy and the resulting V 12Gy in 65 new patients with 138 lesions treated with non-coplanar VMAT technique in our clinic. Conclusions A simple formula is proposed for estimation of the optimal individual RS dose for any given lesion volume for patients with (multiple) BM. This formula is based on calculation of the brain toxicity parameter, V 12Gy , for the normal brain minus PTV.

PURPOSE: We implemented magnetic resonance-guided breath-hold stereotactic body radiation therapy in combination with visual feedback using the MRIdian system. Both accuracy of gated delivery and reproducibility of tumor positions were studied.METHODS AND MATERIALS: Tumor tracking is realized through repeated magnetic resonance imaging in a single sagittal plane at 4 frames per second with deformable image registration. An in-room monitor allowed visualization of the tracked gross tumor volume (GTV) contour and the planning target volume (PTV) (GTV + 3 mm), which was the gating boundary. For each delivery, a predefined threshold-region of interest percentage (ROI%) allows a percentage of GTV area to be outside the gating boundary before a beam-hold is triggered. Accuracy of gated delivery and tumor position reproducibility during breath-holds was analyzed for 15 patients (87 fractions) with lung, adrenal, and pancreas tumors. For each fraction, we analyzed (1) reproducibility of system-tracked GTV centroid position within the PTV; (2) geometric coverage of GTV area within the PTV; (3) treatment duty cycle efficiency; (4) effects of threshold ROI% settings on treatment duty cycle efficiency and GTV area coverage; and (5) beam-off latency effect on mean GTV coverage.RESULTS: For lung, adrenal, and pancreatic tumors, grouped 5th to 95th percentile distributions of GTV centroid positions in the dorsoventral direction, relative to PTV-center of mass (COM), were, respectively, -3.3 mm to 2.8 mm, -2.5 mm to 3.7 mm, and -4.4 mm to 2.9 mm. Corresponding distributions in the craniocaudal direction were -2.6 mm to 4.6 mm, -4.1 mm to 4.4 mm, and -4.4 mm to 4.5 mm, respectively. Mean GTV areas encompassed during beam-on for all fractions were 94.6%, 94.3%, and 95.3% for lung, adrenal, and pancreas tumors, respectively. Mean treatment duty cycle efficiency ranged from 67% to 87% for these tumors. Use of higher threshold-ROI% resulted in increased duty cycle efficiency, at the cost of a small decrease in GTV area coverage. The beam-off latency had a marginal impact on the GTV coverage.CONCLUSIONS: Gated stereotactic body radiation therapy delivery during breath-hold, real-time magnetic resonance guidance resulted in at least 95% geometric GTV coverage in lung, adrenal, and pancreatic tumors.

Background Detection of glioblastoma progression is important for clinical decision-making on cessation or initiation of therapy, for enrollment in clinical trials, and for response measurement in time and location. The RANO-criteria are considered standard for the timing of progression. To evaluate local treatment, we aim to find the most accurate progression location. We determined the differences in progression free survival (PFS) and in tumor volumes at progression (Vprog) by three definitions of progression. Methods In a consecutive cohort of 73 patients with newly-diagnosed glioblastoma between 1/1/2012 and 31/12/2013, progression was established according to three definitions. We determined (1) earliest radiological progression (ERP) by retrospective multidisciplinary consensus review using all available imaging and follow-up, (2) clinical practice progression (CPP) from multidisciplinary tumor board conclusions, and (3) progression by the RANO-criteria. Results ERP was established in 63 (86%), CPP in 64 (88%), RANO progression in 42 (58%). Of the 63 patients who had died, 37 (59%) did with prior RANO-progression, compared to 57 (90%) for both ERP and CPP. The median overall survival was 15.3 months. The median PFS was 8.8 months for ERP, 9.5 months for CPP, and 11.8 months for RANO. The PFS by ERP was shorter than CPP (HR 0.57, 95% CI 0.38–0.84, p = 0.004) and RANO-progression (HR 0.29, 95% CI 0.19–0.43, p

INTRODUCTION: There is an ongoing debate on the optimal treatment for stage I NSCLC, with increasing evidence for comparable health outcomes after surgery and stereotactic body radiation therapy (SBRT). For clinical decision making, the experienced quality of life, summarized as health utility, is of importance to choosing between treatments. In this study, we evaluated differences in longitudinal health utility in stage I NSCLC in the first year after surgical resection versus after SBRT before any recurrence of disease. We also assessed the impact of potential prognostic variables on health utility.METHODS: Prospectively collected databases containing data on patients with stage I NSCLC treated with either SBRT or surgery were pooled from two large hospitals in the Netherlands. Quality of life data were measured by the Quality of Life Questionnaire-Core 30 questionnaire at baseline and 3, 6, and 12 months after treatment. Health utility (measured using the European Quality of Life Five-Dimension questionnaire) was calculated from the Quality of Life Questionnaire-Core 30 questionnaire by using a mapping algorithm. Propensity score matching was used to adjust for selection bias. Treatment effects were estimated for the matched patients by using a longitudinal mixed model approach.RESULTS: After correction for Eastern Cooperative Oncology Group score, sex, and age, the difference in 1-year averaged health utility between the SBRT and surgery groups was 0.026 (95% confidence interval: 0.028-0.080). Differences in health utility decreased over time.CONCLUSIONS: A small but not statistically significant difference in health utility was found between patients with stage I NSCLC treated with surgery and those treated with SBRT. Current analysis strengthens existing evidence that SBRT is an equivalent treatment option for early-stage NSCLC. Comparative cost-effectiveness remains to be determined.

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

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.

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.