Statistical breathing curve sampling to quantify interplay effects of moving lung tumors in a 4D Monte Carlo dose calculation framework.

PURPOSE: The interplay between respiratory tumor motion and dose application by intensity modulated radiotherapy (IMRT) techniques can potentially lead to undesirable and non-intuitive deviations from the planned dose distribution. We developed a 4D Monte Carlo (MC) dose recalculation framework featuring statistical breathing curve sampling, to precisely simulate the dose distribution for moving target volumes aiming at a comprehensive assessment of interplay effects. METHODS: We implemented a dose accumulation tool that enables dose recalculations of arbitrary breathing curves including the actual breathing curve of the patient. This MC dose recalculation framework is based on linac log-files, facilitating a high temporal resolution up to 0.1 s. By statistical analysis of 128 different breathing curves, interplay susceptibility of different treatment parameters was evaluated for an exemplary patient case. To facilitate prospective clinical application in the treatment planning stage, in which patient breathing curves or linac log-files are not available, we derived a log-file free version with breathing curves generated by a random walk approach. Interplay was quantified by standard deviations σ in D5%, D50% and D95%. RESULTS: Interplay induced dose deviations for single fractions were observed and evaluated for IMRT and volumetric arc therapy (σD95% up to 1.3 %) showing a decrease with higher fraction doses and an increase with higher MU rates. Interplay effects for conformal treatment techniques were negligible (σ<0.1%). The log-file free version and the random walk generated breathing curves yielded similar results (deviations in σ< 0.1 %) and can be used as substitutes for interplay assessment. CONCLUSION: It is feasible to combine statistically sampled breathing curves with MC dose calculations. The universality of the presented framework allows comprehensive assessment of interplay effects in retrospective and prospective clinically relevant scenarios.

ESTRO ACROP and SIOPE recommendations for myeloablative Total Body Irradiation in children.

BACKGROUND AND PURPOSE: Myeloablative Total Body Irradiation (TBI) is an important modality in conditioning for allogeneic hematopoietic stem cell transplantation (HSCT), especially in children with high-risk acute lymphoblastic leukemia (ALL). TBI practices are heterogeneous and institution-specific. Since TBI is associated with multiple late adverse effects, recommendations may help to standardize practices and improve the outcome versus toxicity ratio for children. MATERIAL AND METHODS: The European Society for Paediatric Oncology (SIOPE) Radiotherapy TBI Working Group together with ESTRO experts conducted a literature search and evaluation regarding myeloablative TBI techniques and toxicities in children. Findings were discussed in bimonthly virtual meetings and consensus recommendations were established. RESULTS: Myeloablative TBI in HSCT conditioning is mostly performed for high-risk ALL patients or patients with recurring hematologic malignancies. TBI is discouraged in children <3-4 years old because of increased toxicity risk. Publications regarding TBI are mostly retrospective studies with level III-IV evidence. Preferential TBI dose in children is 12-14.4 Gy in 1.6-2 Gy fractions b.i.d. Dose reduction should be considered for the lungs to <8 Gy, for the kidneys to ≤10 Gy, and for the lenses to <12 Gy, for dose rates ≥6 cGy/min. Highly conformal techniques i.e. TomoTherapy and VMAT TBI or Total Marrow (and/or Lymphoid) Irradiation as implemented in several centers, improve dose homogeneity and organ sparing, and should be evaluated in studies. CONCLUSIONS: These ESTRO ACROP SIOPE recommendations provide expert consensus for conventional and highly conformal myeloablative TBI in children, as well as a supporting literature overview of TBI techniques and toxicities.

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions.

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

Towards homogenization of total body irradiation practices in pediatric patients across SIOPE affiliated centers. A survey by the SIOPE radiation oncology working group.

BACKGROUND AND PURPOSE: To reduce relapse risk, Total Body Irradiation (TBI) is part of conditioning regimens for hematopoietic stem cell transplantation (HSCT) in pediatric acute leukemia. The study purpose was to evaluate clinical practices regarding TBI, such as fractionation, organ shielding and delivery techniques, among SIOPE affiliated radiotherapy centers. METHODS: An electronic survey was sent out to 233 SIOPE affiliated centers, containing 57 questions about clinical practice of TBI. Surveys could be answered anonymously. RESULTS: From over 25 countries, 82 responses were collected. For TBI-performing centers, 40/48 irradiated ≤10 pediatric patients annually (range: 1-2 to >25). Most indications concerned acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML). Four different fractionation schedules were used, of which 12 Gy in 6 fractions was applied in 91% for ALL and 86% for AML. Dose reduction to the lungs, mostly to a mean dose of 8-10 Gy, was applied by 28/33 centers for ALL and 19/21 centers for AML, in contrast to much less applied dose reduction to the kidneys (7/33 ALL and 7/21 AML), thyroid (2/33 ALL and 2/21 AML), liver (4/33 ALL and 3/21 AML) and lenses (4/33 ALL and 4/21 AML). Conventional TBI techniques were used by 24/29 responding centers, while 5/29 used advanced optimized planning techniques. CONCLUSION: Across SIOPE, there is a high level of uniformity in fractionation and use of lung shielding. Practices vary regarding other organs-at-risk shielding and implementation of advanced techniques. A SIOPE radiotherapy working group will be established to define international guidelines for pediatric TBI.

Novel rotatable tabletop for total-body irradiation using a linac-based VMAT technique.

BACKGROUND: Volumetric Modulated Arc Therapy (VMAT) techniques have recently been implemented in clinical practice for total-body irradiation (TBI). To date, most techniques still use special couches, translational tables, or other self-made immobilization devices for dose delivery. Aim of the present study was to report the first results of a newly developed rotatable tabletop designed for VMAT-TBI. METHODS: The VMAT-TBI technique theoretically allows the use of any standard positioning device at the linear accelerator. Nevertheless, the main problem is that patients taller than 120 cm cannot be treated in one position due to the limited cranial-caudal couch shift capacities of the linac. Therefore, patients are usually turned from a head-first supine position (HFS) to a feet-first supine position (FFS) to overcome this limitation. The newly developed rotatable tabletop consists completely of carbon fiber, including the ball bearing within the base plate of the rotation unit. The patient can be turned 180° from a HFS to a FFS position within a few seconds, without the need of repositioning. RESULTS: The first 20 patients had a median age of 47 years, and received TBI before bone marrow transplantation for acute myeloid leukemia. Most patients (13/20) received a TBI dose of 4 Gy in 2 fractions, twice daily. The mean number of applied monitor units (MU) was 6476 MU using a multi-arcs and multi-isocenter VMAT-TBI technique. The tabletop has been successfully used in daily clinical practice and helped to keep the treatment times at an acceptable level. During the first treatment fraction, the mean overall treatment time (OTT) was 57 min. Since no additional image guidance was used in fraction 2 of the same day, the OTT was reduced to mean 38 min. CONCLUSIONS: The easy and reproducible rotation of the patient on the treatment couch using the rotatable tabletop, is time-efficient and overcomes the need of repositioning the patient after turning from a HFS to a FFS position during VMAT TBI. Furthermore, it prevents couch-gantry collisions, incorrect isocenter shifts and beam mix-up due to predicted absolute table coordinates, which are recorded to the R + V system with the corresponding beams.

Fast oxygen-enhanced multislice imaging of the lung using parallel acquisition techniques.

The purpose of this study was to evaluate an optimized multislice acquisition technique for oxygen-enhanced MRI of the lung using slice-selective inversion and refocusing pulses in combination with parallel imaging. An inversion recovery HASTE sequence was implemented with respiratory triggering to perform imaging in end-expiration and with ECG triggering to avoid image acquisition during the systolic phase. Inversion pulses and the readout of echo trains could be interleaved to decrease acquisition time. The sequence was evaluated in 15 healthy volunteers, comparing three acquisition schemes: (1) acquisition of four slices without parallel imaging; (2) acquisition of four slices with parallel imaging; (3) acquisition of six slices with parallel imaging. These multislice acquisitions were repeated 80 times with alternating inhalation of room air and oxygen. The oxygen-induced signal increase showed no significant difference with and without parallel imaging. However, only with parallel imaging did the interleaved acquisition of six or more slices become possible, thus enabling a more complete anatomic coverage of the lung. The average required end-expiration time per repetition to acquire six slices could be significantly reduced from 4112 ms without to 2727 ms with parallel imaging. Total acquisition time varied between 8 and 13 min depending on the respiratory frequency.

Oxygen-enhanced MRI of the brain.

Blood oxygenation level-dependent (BOLD) contrast MRI is a potential method for a physiological characterization of tissue beyond mere morphological representation. The purpose of this study was to develop evaluation techniques for such examinations using a hyperoxia challenge. Administration of pure oxygen was applied to test these techniques, as pure oxygen can be expected to induce relatively small signal intensity (SI) changes compared to CO(2)-containing gases and thus requires very sensitive evaluation methods. Fourteen volunteers were investigated by alternating between breathing 100% O(2) and normal air, using two different paradigms of administration. Changes ranged from >30% in large veins to 1.71% +/- 0.14% in basal ganglia and 0.82% +/- 0.08% in white matter. To account for a slow physiological response function, a reference for correlation analysis was derived from the venous reaction. An objective method is presented that allows the adaptation of the significance threshold to the complexity of the paradigm used. Reference signal characteristics in representative brain tissue regions were established. As the presented evaluation scheme proved its applicability to small SI changes induced by pure oxygen, it can readily be used for similar experiments with other gases.