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This study evaluated the robustness of multi-isocenter Volumetric Modulated Arc Therapy Total Body Irradiation dose distribution in the overlapping region between the head-first and feet-first computed tomography scans, considering the longitudinal isocenter shifts recorded during treatment delivery. For 15 out of 22 patients, the dose distribution in the overlapping region fulfilled all three the robustness criteria. The overlapping region dose distribution of the remaining 7 cases fulfilled two robustness criteria. The dose distribution was found to be robust against daily recorded longitudinal isocenter shifts, as a consequence of the patient position verification procedure, of up to 16 mm., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Background: In pediatric radiotherapy treatment planning of abdominal tumors, dose constraints to the pancreatic tail/spleen are applied to reduce late toxicity. In this study, an analysis of inter- and intrafraction motion of the pancreatic tail/spleen is performed to estimate the potential benefits of online MRI-guided radiotherapy (MRgRT)., Materials and Methods: Ten randomly selected neuroblastoma patients (median age: 3.4 years), irradiated with intensity-modulated arc therapy at our department (prescription dose: 21.6/1.8 Gy), were retrospectively evaluated for inter- and intrafraction motion of the pancreatic tail/spleen. Three follow-up MRIs (T2- and T1-weighted ± gadolinium) were rigidly registered to a planning CT (pCT), on the vertebrae around the target volume. The pancreatic tail/spleen were delineated on all MRIs and pCT. Interfraction motion was defined as a center of gravity change between pCT and T2-weighted images in left-right (LR), anterior-posterior (AP) and cranial-caudal (CC) direction. For intrafraction motion analysis, organ position on T1-weighted ± gadolinium was compared to T2-weighted. The clinical radiation plan was used to estimate the dose received by the pancreatic tail/spleen for each position., Results: The median (IQR) interfraction motion was minimal in LR/AP, and largest in CC direction; pancreatic tail 2.5 mm (8.9), and spleen 0.9 mm (3.9). Intrafraction motion was smaller, but showed a similar motion pattern (pancreatic tail, CC: 0.4 mm (1.6); spleen, CC: 0.9 mm (2.8)). The differences of Dmean associated with inter- and intrafraction motions ranged from - 3.5 to 5.8 Gy for the pancreatic tail and - 1.2 to 3.0 Gy for the spleen. In 6 out of 10 patients, movements of the pancreatic tail and spleen were highlighted as potentially clinically significant because of ≥ 1 Gy dose constraint violation., Conclusion: Inter- and intrafraction organ motion results into unexpected constrain violations in 60% of a randomly selected neuroblastoma cohort, supporting further prospective exploration of MRgRT., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: Optic nerves are part of the craniospinal irradiation (CSI) target volume. Modern radiotherapy techniques achieve highly conformal target doses while avoiding organs-at-risk such as the lens. The magnitude of eye movement and its influence on CSI target- and avoidance volumes are unclear. We aimed to evaluate the movement-range of lenses and optic nerves and its influence on dose distribution of several planning techniques., Methods: Ten volunteers underwent MRI scans in various gaze directions (neutral, left, right, cranial, caudal). Lenses, orbital optic nerves, optic discs and CSI target volumes were delineated. 36-Gy cranial irradiation plans were constructed on synthetic CT images in neutral gaze, with Volumetric Modulated Arc Therapy, pencil-beam scanning proton therapy, and 3D-conventional photons. Movement-amplitudes of lenses and optic discs were analyzed, and influence of gaze direction on lens and orbital optic nerve dose distribution., Results: Mean eye structures' shift from neutral position was greatest in caudal gaze; -5.8±1.2 mm (±SD) for lenses and 7.0±2.0 mm for optic discs. In 3D-conventional plans, caudal gaze decreased Mean Lens Dose (MLD). In VMAT and proton plans, eye movements mainly increased MLD and diminished D98 orbital optic nerve (D98 OON ) coverage; mean MLD increased up to 5.5 Gy [total ΔMLD range -8.1 to 10.0 Gy], and mean D98 OON decreased up to 3.3 Gy [total ΔD98 OON range -13.6 to 1.2 Gy]. VMAT plans optimized for optic disc Internal Target Volume and lens Planning organ-at-Risk Volume resulted in higher MLD over gaze directions. D98 OON became ≥95% of prescribed dose over 95/100 evaluated gaze directions, while all-gaze bilateral D98 OON significantly changed in 1 of 10 volunteers., Conclusion: With modern CSI techniques, eye movements result in higher lens doses and a mean detriment for orbital optic nerve dose coverage of <10% of prescribed dose., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background and Purpose: Magnetic resonance guided radiotherapy (MRgRT) has been successfully implemented for several routine clinical applications in adult patients. The purpose of this study is to map the potential benefit of MRgRT on toxicity reduction and outcome in pediatric patients treated with curative intent for primary and metastatic sites., Materials and Methods: Between May and August 2020, a survey was distributed among SIOPE- and COG-affiliated radiotherapy departments, treating at least 25 pediatrics patients annually and being (candidate) users of a MRgRT system. The survey consisted of a table with 45 rows (clinical scenarios for primary (n = 28) and metastatic (n = 17) tumors) and 7 columns (toxicity reduction, outcome improvement, PTV margin reduction, target volume daily adaptation, online re-planning, intrafraction motion compensation and on-board functional imaging) and the option to answer by 'yes/no' . Afterwards, the Dutch national radiotherapy cohort was used to estimate the percentage of pediatric treatments that may benefit from MRgRT., Results: The survey was completed by 12/17 (71% response rate) institutions meeting the survey inclusion criteria. Responders indicated an 'expected benefit' from MRgRT for toxicity/outcome in 7% (for thoracic lymphomas and abdominal rhabdomyosarcomas)/0% and 18% (for mediastinal lymph nodes, lymph nodes located in the liver/splenic hilum, and liver metastases)/0% of the considered scenarios for the primary and metastatic tumor sites, respectively, and a 'possible benefit' was estimated in 64%/46% and 47%/59% of the scenarios. When translating the survey outcome into a clinical perspective a toxicity/outcome benefit, either expected or possible, was anticipated for 55%/24% of primary sites and 62%/38% of the metastatic sites., Conclusion: Although the benefit of MRgRT in pediatric radiation oncology is estimated to be modest, the potential role for reducing toxicity and improving clinical outcomes warrants further investigation. This fits best within the context of prospective studies or registration trials., Competing Interests: Dr. Hall reports an Honorarium from Accuray, Inc for Serving on the Scientific Review Committee, AERO 2019 Meeting. All other authors declared that there are no conflict of interest., (© 2021 The Author(s).)

Background: For decades, Anterior-Posterior/Posterior-Anterior (AP/PA) photon beams were standard-of-care for flank irradiation in children with renal cancer. Recently, highly conformal flank target volumes were defined correcting for postoperative organ shift and intra-fraction motion.By radiotherapy treatment plan comparison, this study aims to estimate the clinical benefits and potential risks of combining highly conformal target volumes with Volumetric-Modulated Arc Therapy (VMAT) versus conventional target volumes with AP/PA beams for flank irradiation., Materials and Methods: Twenty consecutive renal tumor cases (left/right-sided:10/10; median age:3.2 years) were selected. Highly conformal flank target volumes were generated for VMAT, while conventional target volumes were used for AP/PA. For each case, the dose to the organs at risk (OARs) and Total Body Volume (TBV) was calculated to compare VMAT with AP/PA treatment plans for a prescribed dose (PD) of 14.4/1.8 Gy. Dose constraint violation of the tail of the pancreas and spleen (D mean  < 10 Gy), heart (D 50  < 5 Gy) or mammary buds (D mean  < 10 Gy) were prioritized as potentially beneficial for clinics., Results: Highly conformal Planning Target Volumes (PTV) were smaller than conventional volumes (mean ΔPTV AP/PA -PTV VMAT : 555 mL, Δ60%, p=<0.01). A mean dose reduction favoring VMAT was observed for almost all OARs. Dose constraints to the tail of the pancreas, spleen, heart and mammary buds were fulfilled in 8/20, 12/20, 16/20 and 19/20 cases with AP/PA, versus 14/20, 17/20, 20/20 and 20/20 cases with VMAT, respectively. In 12/20 cases, VMAT prevented the dose constraint violation of one or more OARs otherwise exceeded by AP/PA. VMAT increased the TBV receiving 10% of the PD, but reduced the amount of irradiated TBV for all higher doses., Conclusion: Compared to 14.4 Gy flank irradiation using conventional AP/PA photon beams, an estimated clinical benefit by dose reduction to the OARs can be expected in 60% of the pediatric renal tumor cases using highly conformal flank target volumes combined with VMAT., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background and Purpose: Recently, the SIOP-RTSG developed a highly-conformal flank target volume definition for children with renal tumors. The aims of this study were to evaluate the inter-clinician delineation variation of this new target volume definition in an international multicenter setting and to explore the necessity of quality assurance., Materials and Methods: Six pediatric renal cancer cases were transferred to ten radiation oncologists from seven European countries ('participants'). These participants delineated the pre- and postoperative Gross Tumor Volume (GTV pre/post ), and Clinical Target Volume (CTV) during two test phases (case 1-2 and 3-4), followed by guideline refinement and a quality assurance phase (case 5-6). Reference target volumes (TV ref ) were established by three experienced radiation oncologists. The Dice Similarity Coefficient between the reference and participants (DSC ref/part ) was calculated per case. Delineations of case 5-6 were graded by four independent reviewers as 'per protocol' (0-4 mm), 'minor deviation' (5-9 mm) or 'major deviation' (≥10 mm) from the delineation guideline using 18 standardized criteria. Also, a major deviation resulting in underestimation of the CTV ref was regarded as an unacceptable variation., Results: A total of 57/60 delineation sets were completed. The median DSC ref/part for the CTV was 0.55 without improvement after sequential cases (case 3-4 vs. case 5-6: p = 0.15). For case 5-6, a major deviation was found for 5/18, 12/17, 18/18 and 4/9 collected delineations of the GTV pre , GTV post , CTV-T and CTV-N, respectively. An unacceptable variation from the CTV ref was found for 7/9 participants for case 5 and 6/9 participants for case 6., Conclusion: This international multicenter delineation exercise demonstrates that the new consensus for highly-conformal postoperative flank target volume delineation leads to geometrical variation among participants. Moreover, standardized review showed an unacceptable delineation variation in the majority of the participants. These findings strongly suggest the need for additional training and centralized pre-treatment review when this target volume delineation approach is implemented on a larger scale., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background and Purpose: When using an immobilization mask, a magnetic resonance imaging (MRI) head receive coil cannot be used and patients may experience discomfort during the examination. We therefore wish to assess the added value of an immobilization mask during all MRI scans intended for cranial stereotactic radiotherapy (SRT) planning., Materials and Methods: An MRI was acquired with and without a thermoplastic immobilization mask in ten patients eligible for SRT. A planning computed tomography (CT) scan was also made, to which the two MRIs were independently registered. Additionally, the MRI without immobilization was registered to the MRI in mask. On each sequence, gross tumour volume (GTV), the right eye, brain stem and chiasm were delineated. The absolute differences in centre-of-gravity coordinates and Dice coefficients of the volumes of the delineated structures between the two MRIs were compared., Results: Differences in GTV volume between the two MRIs were low, with median Dice coefficients between 0.88 and 0.91. Similarly, the median absolute differences in centre-of-gravity coordinates between the GTVs, organs at risk and landmarks delineated on the two MRIs were within 0.5 mm. The 95% confidence intervals of the median absolute differences in the three GTV coordinates was within 1 mm, which corresponds to the target volume safety margin used to account for possible errors during the SRT treatment chain., Conclusions: The effect of scanning a patient without the immobilization mask falls within acceptable bounds of error for the geometrical accuracy of the SRT treatment chain. Consequently, placing the head in treatment position during all MRI scans for patients undergoing radiotherapy of brain metastasis is deemed unnecessary., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Background: Stereotactic radiotherapy (SBRT) might improve pain and local control in patients with bone metastases compared to conventional radiotherapy, although an overall estimate of these outcomes is currently unknown., Methods: A systematic review was carried out following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pubmed, Embase, and Cochrane databases were systematically searched to identify studies reporting pain response and local control among patients with bone metastases from solid-organ tumors who underwent SBRT in 1-6 fractions. All studies prior to April 15, 2017, were included. Study quality was assessed by predefined criteria, and pain response and local control rates were extracted., Results: A total of 2619 studies were screened; 57 were included (reporting outcomes for 3995 patients) of which 38 reported pain response and 45 local control rates. Local control rates were high with pain response rates above those previously reported for conventional radiotherapy. Marked heterogeneity in study populations and delivered treatments were identified such that quantitative synthesis was not appropriate. Reported toxicity was limited. Of the pain response studies, 73.7% used a retrospective cohort design and only 10.5% used the international consensus endpoint definitions of pain response. The median survival within the included studies ranged from 8 to 30.4 months, suggesting a high risk of selection bias in the included observational studies., Conclusions: This review demonstrates the potential benefit of SBRT over conventional palliative radiotherapy in improving pain due to bone metastases. Given the methodological limitations of the published literature, however, large randomized trials are now urgently required to better quantify this benefit., (© The Author(s) 2019. Published by Oxford University Press.)

In brain/head-and-neck radiotherapy (RT), thermoplastic immobilization masks guarantee reproducible patient positioning in treatment position between MRI, CT, and irradiation. Since immobilization masks do not fit in the diagnostic MR head/head-and-neck coils, flexible surface coils are used for MRI imaging in clinical practice. These coils are placed around the head/neck, in contact with the immobilization masks. However, the positioning of these flexible coils is technician dependent, thus leading to poor image reproducibility. Additionally, flexible surface coils have an inferior signal-to-noise-ratio (SNR) compared to diagnostic coils. The aim of this work was to create a new immobilization setup which fits into the diagnostic MR coils in order to enhance MR image quality and reproducibility. For this purpose, a practical immobilization setup was constructed. The performances of the standard clinical and the proposed setups were compared with four tests: SNR, image quality, motion restriction, and reproducibility of inter-fraction subject positioning. The new immobilization setup resulted in 3.4 times higher SNR values on average than the standard setup, except directly below the flexible surface coils where similar SNR was observed. Overall, the image quality was superior for brain/head-and-neck images acquired with the proposed RT setup. Comparable motion restriction in feet-head/left-right directions (maximum motion ≈1 mm) and comparable inter-fraction repositioning accuracy (mean inter-fraction movement 1 ± 0.5 mm) were observed for the standard and the new setup.

Background: Routine treatment for unstable spinal metastases consists of surgical stabilization followed by external beam radiotherapy (EBRT) or stereotactic body radiotherapy (SBRT) after a minimum of 1-2 weeks to allow for initial wound healing. Although routine treatment, there are several downsides. First, radiotherapy induced pain relief is delayed by the time interval required for wound healing. Second, EBRT often requires multiple hospital visits and only 60% of the patients experience pain relief. Third, spinal implants cause imaging artifacts hindering SBRT treatment planning and delivery. Reversing the order of surgery and radiotherapy, with dose sparing of the surgical area by SBRT, could overcome these disadvantages and by eliminating the interval between the two treatments, recovery, and palliation may occur earlier. Design: The safety of SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases was investigated. Safety was evaluated using the Common-Toxicity-Criteria-Adverse-Events-4.0, with the occurrence of wound complications within 90-days being the primary concern. Results: Between June-2015 and January-2017, 13 patients underwent SBRT followed by surgical stabilization for unstable spinal metastases. The median time between SBRT and surgery was 17-h (IQR 5-19). None of the patients experienced wound complications. Improvements in pain and quality of life were observed over time for all patients. Conclusion: SBRT followed by surgical stabilization within 24 h for the treatment of unstable spinal metastases is safe. Palliation may be experienced earlier and with both treatments being performed in one hospital admission the treatment burden decreases.

Background and Purpose: Local implementation of plan-specific quality assurance (QA) methods for intensity-modulated radiotherapy (IMRT) and volumetric modulated arc therapy (VMAT) treatment plans may vary because of dissimilarities in procedures, equipment and software. The purpose of this work is detecting possible differences between local QA findings and those of an audit, using the same set of treatment plans., Methods: A pre-defined set of clinical plans was devised and imported in the participating institute's treatment planning system for dose computation. The dose distribution was measured using an ionisation chamber, radiochromic film and an ionisation chamber array. The centres performed their own QA, which was compared to the audit findings. The agreement/disagreement between the audit and the institute QA results were assessed along with the differences between the dose distributions measured by the audit team and computed by the institute., Results: For the majority of the cases the results of the audit were in agreement with the institute QA findings: ionisation chamber: 92%, array: 88%, film: 76% of the total measurements. In only a few of these cases the evaluated measurements failed for both: ionisation chamber: 2%, array: 4%, film: 0% of the total measurements., Conclusion: Using predefined treatment plans, we found that in approximately 80% of the evaluated measurements the results of local QA of IMRT and VMAT plans were in line with the findings of the audit. However, the percentage of agreement/disagreement depended on the characteristics of the measurement equipment used and on the analysis metric., (© 2018 The Authors.)

Background: Standard radiotherapy is the treatment of first choice in patients with symptomatic spinal metastases, but is only moderately effective. Stereotactic body radiation therapy is increasingly used to treat spinal metastases, without randomized evidence of superiority over standard radiotherapy. The VERTICAL study aims to quantify the effect of stereotactic radiation therapy in patients with metastatic spinal disease., Methods/design: This study follows the 'cohort multiple Randomized Controlled Trial' design. The VERTICAL study is conducted within the PRESENT cohort. In PRESENT, all patients with bone metastases referred for radiation therapy are enrolled. For each patient, clinical and patient-reported outcomes are captured at baseline and at regular intervals during follow-up. In addition, patients give informed consent to be offered experimental interventions. Within PRESENT, 110 patients are identified as a sub cohort of eligible patients (i.e. patients with unirradiated painful, mechanically stable spinal metastases who are able to undergo stereotactic radiation therapy). After a protocol amendment, also patients with non-spinal bony metastases are eligible. From the sub cohort, a random selection of patients is offered stereotactic radiation therapy (n = 55), which patients may accept or refuse. Only patients accepting stereotactic radiation therapy sign informed consent for the VERTICAL trial. Non-selected patients (n = 55) receive standard radiotherapy, and are not aware of them serving as controls. Primary endpoint is pain response after three months. Data will be analyzed by intention to treat, complemented by instrumental variable analysis in case of substantial refusal of the stereotactic radiation therapy in the intervention arm., Discussion: This study is designed to quantify the treatment response after (stereotactic) radiation therapy in patients with symptomatic spinal metastases. This is the first randomized study in palliative care following the cohort multiple Randomized Controlled Trial design. This design addresses common difficulties associated with classic pragmatic randomized controlled trials, such as disappointment bias in patients allocated to the control arm, slow recruitment, and poor generalizability., Trial Registration: The Netherlands Trials Register number NL49316.041.14. ClinicalTrials.gov registration number NCT02364115 . Date of trial registration February 1, 2015.

Background: Treatment for locally advanced rectal cancer (LARC) consists of chemoradiation therapy (CRT) and surgery. Approximately 15% of patients show a pathological complete response (pCR). Increased pCR-rates can be achieved through dose escalation, thereby increasing the number patients eligible for organ-preservation to improve quality of life (QoL). A randomized comparison of 65 versus 50Gy with external-beam radiation alone has not yet been performed. This trial investigates pCR rate, clinical response, toxicity, QoL and (disease-free) survival in LARC patients treated with 65Gy (boost + chemoradiation) compared with 50Gy standard chemoradiation (sCRT)., Methods/design: This study follows the 'cohort multiple randomized controlled trial' (cmRCT) design: rectal cancer patients are included in a prospective cohort that registers clinical baseline, follow-up, survival and QoL data. At enrollment, patients are asked consent to offer them experimental interventions in the future. Eligible patients-histologically confirmed LARC (T3NxM0 <1 mm from mesorectal fascia, T4NxM0 or TxN2M0) located ≤10 cm from the anorectal transition who provided consent for experimental intervention offers-form a subcohort (n = 120). From this subcohort, a random sample is offered the boost prior to sCRT (n = 60), which they may accept or refuse. Informed consent is signed only after acceptance of the boost. Non-selected patients in the subcohort (n = 60) undergo sCRT alone and are not notified that they participate in the control arm until the trial is completed. sCRT consists of 50Gy (25 × 2Gy) with concomitant capecitabine. The boost (without chemotherapy) is given prior to sCRT and consists of 15 Gy (5 × 3Gy) delivered to the gross tumor volume (GTV). The primary endpoint is pCR (TRG 1). Secondary endpoints include acute grade 3-4 toxicity, good pathologic response (TRG 1-2), clinical response, surgical complications, QoL and (disease-free) survival. Data is analyzed by intention to treat., Discussion: The boost is delivered prior to sCRT so that GTV adjustment for tumor shrinkage during sCRT is not necessary. Small margins also aim to limit irradiation of healthy tissue. The cmRCT design provides opportunity to overcome common shortcomings of classic RCTs, such as slow recruitment, disappointment-bias in control arm patients and poor generalizability., Trial Registration: The Netherlands Trials Register NL46051.041.13. Registered 22 August 2013. ClinicalTrials.gov NCT01951521 . Registered 18 September 2013.

The effects of commercial and crystalline solutions of chloroprocaine (CP) (1.6 X 10(-3)-0.4 X 10(-3)M) and sodium bisulfite (SB) (0.8 X 10(-3)-0.08 X 10(-3)M) were studied on the multiplication of human neuroblastoma cells. These cells were chosen because of putative neurotoxicity associated with CP; cell multiplication (measured as colony-forming ability-CFA) was studied because CFA is a reliable in vitro test for drug toxicity at the cellular level. CFA was dramatically reduced (86%) after 20-hr exposure to commercial solutions of CP. Shorter exposure times (3 hr) resulted in a marginal toxic effect (32%). At similar concentrations and after 20-hr exposure time, CP crystalline solutions induced a 37.5% inhibition that decreased with decreased time in culture. Sodium bisulfite reduced cell multiplication to a degree that varied with different samples of SB. With a 3-hr exposure time, CFA was reduced 72-92% by SB-1 and 57-72% by SB-2. The variability of SB toxicity and the difference in toxicity with commercial and crystalline solutions of CP are discussed in terms of possible clinical toxicity.