Clinical practice in European centres treating paediatric posterior fossa tumours with pencil beam scanning proton therapy.

BACKGROUND AND PURPOSE: As no guidelines for pencil beam scanning (PBS) proton therapy (PT) of paediatric posterior fossa (PF) tumours exist to date, this study investigated planning techniques across European PT centres, with special considerations for brainstem and spinal cord sparing. MATERIALS AND METHODS: A survey and a treatment planning comparison were initiated across nineteen European PBS-PT centres treating paediatric patients. The survey assessed all aspects of the treatment chain, including but not limited to delineations, dose constraints and treatment planning. Each centre planned two PF tumour cases for focal irradiation, according to their own clinical practice but based on common delineations. The prescription dose was 54 Gy(RBE) for Case 1 and 59.4 Gy(RBE) for Case 2. For both cases, planning strategies and relevant dose metrics were compared. RESULTS: Seventeen (89 %) centres answered the survey, and sixteen (80 %) participated in the treatment planning comparison. In the survey, thirteen (68 %) centres reported using the European Particle Therapy Network definition for brainstem delineation. In the treatment planning study, while most centres used three beam directions, their configurations varied widely across centres. Large variations were also seen in brainstem doses, with a brainstem near maximum dose (D2%) ranging from 52.7 Gy(RBE) to 55.7 Gy(RBE) (Case 1), and from 56.8 Gy(RBE) to 60.9 Gy(RBE) (Case 2). CONCLUSION: This study assessed the European PBS-PT planning of paediatric PF tumours. Agreement was achieved in e.g. delineation-practice, while wider variations were observed in planning approach and consequently dose to organs at risk. Collaboration between centres is still ongoing, striving towards common guidelines.

Stopping-power ratio estimation for proton radiotherapy using dual-energy computed tomography and prior-image constrained denoising.

BACKGROUND: Dual-energy computed tomography (DECT) is a promising technique for estimating stopping-power ratio (SPR) for proton therapy planning. It is known, however, that deriving electron density (ED) and effective atomic number (EAN) from DECT data can cause noise amplification in the resulting SPR images. This can negate the benefits of DECT. PURPOSE: This work introduces a new algorithm for estimating SPR from DECT with noise suppression, using a pair of CT scans with spectral separation. The method is demonstrated using phantom measurements. MATERIALS AND METHODS: An iterative algorithm is presented, reconstructing ED and EAN with noise suppression, based on Prior Image Constrained Denoising (PIC-D). The algorithm is tested using a Siemens Definition AS+ CT scanner (Siemens Healthcare, Forchheim, Germany). Three phantoms are investigated: a calibration phantom (CIRS 062M), a QA phantom (CATPHAN 700), and an anthropomorphic head phantom (CIRS 731-HN). A task-transfer function (TTF) and the noise power spectrum are derived from SPR images of the QA phantom for the evaluation of image quality. Comparisons of accuracy and noise for ED, EAN, and SPR are made for various versions of the algorithm in comparison to a solution based on Siemens syngo.via Rho/Z software and the current clinical standard of a single-energy CT stoichiometric calibration. A gamma analysis is also applied to the SPR images of the head phantom and water-equivalent distance (WED) is evaluated in a treatment planning system for a proton treatment field. RESULTS: The algorithm is effective at suppressing noise in both ED and EAN and hence also SPR. The noise is tunable to a level equivalent to or lower than that of the syngo.via Rho/Z software. The spatial resolution (10% and 50% frequencies in the TTF) does not degrade even for the highest noise suppression investigated, although the average spatial frequency of noise does decrease. The PIC-D algorithm showed better accuracy than syngo.via Rho/Z for low density materials. In the calibration phantom, it was superior even when excluding lung substitutes, with root-mean-square deviations for ED and EAN less than 0.3% and 2%, respectively, compared to 0.5% and 3%. In the head phantom, however, the SPR accuracy of the PIC-D algorithm was comparable (excluding sinus tissue) to that derived from syngo.via Rho/Z: less than 1% error for soft tissue, brain, and trabecular bone substitutes and 5-7% for cortical bone, with the larger error for the latter likely related to the phantom geometry. Gamma evaluation showed that PIC-D can suppress noise in a patient-like geometry without introducing substantial errors in SPR. The absolute pass rates were almost identical for PIC-D and syngo.via Rho/Z. In the WED evaluations no general differences were shown. CONCLUSIONS: The PIC-D DECT algorithm provides scanner-specific calibration and tunable noise suppression. It is vendor agnostic and applicable to any pair of CT scans with spectral separation. Improved accuracy to current methods was not clearly demonstrated for the complex geometry of a head phantom, but the suppression of noise without spatial resolution degradation and the possibility of incorporating constraints on image properties, suggests the usefulness of the approach.

Effects of enrichment strategies on outcome of adrecizumab treatment in septic shock: Post-hoc analyses of the phase II adrenomedullin and outcome in septic shock 2 trial.

Purpose: Adrecizumab, a non-neutralizing antibody of adrenomedullin (ADM) was recently investigated regarding its potential to restore endothelial barrier function in septic shock patients with high plasma ADM levels. Circulating dipeptidyl peptidase 3 (cDPP3), a protease involved in the degradation of several cardiovascular mediators, represents another biological pathway strongly associated with outcome in septic shock, although unrelated to ADM. Therefore, the prognosis of patients with elevated cDPP3 may not be influenced by Adrecizumab. Also, time until initiation of treatment may influence efficacy. Objective: To evaluate effects of cDPP3-based enrichment on treatment efficacy of Adrecizumab. Materials and Methods: Post-hoc analysis of AdrenOSS-2, a phase-II, double-blind, randomized, placebo-controlled biomarker-guided trial of Adrecizumab. Results: Compared to the total study cohort [HR for 28-day mortality of 0.84 (95% CI 0.53;1.31), p = 0.439], therapeutic benefit of Adrecizumab tended to be more pronounced in the subgroup of 249 patients with low cDPP3 (<50 ng/mL); [HR of 0.61 (95% CI 0.34;1.08), p = 0.085]. Median duration to study drug infusion was 8.5 h. In the subgroup of 129 patients with cDPP3 <50 ng/mL and an early start of treatment (<8.5 h after septic shock diagnosis) HR for 28-day mortality vs. placebo was 0.49 (95% CI 0.21-1.18), p = 0.105. In multivariate interaction analyses corrected for baseline disease severity, both cDPP3, as well as the cDPP3 * treatment interaction term were associated with a reduced HR for 28-day mortality in the Adrecizumab treated group; p = 0.015 for cDPP3 in univariate analysis, p = 0.025 for the interaction term between cDPP3 and treatment group. In contrast, treatment timing was not significantly associated with 28-day mortality in multivariate interaction analyses. Discussion: In septic shock patients with high ADM levels, a further post-hoc enrichment strategy based on cDPP3 may indicate (with all the caveats to be considered for post-hoc subgroup analyses) that therapeutic efficacy is most pronounced in patients with lower cDPP3 levels.

DMLC motion tracking of moving targets for intensity modulated arc therapy treatment: a feasibility study.

PURPOSE: Intensity modulated arc therapy offers great advantages with the capability of delivering a fast and highly conformal treatment. However, moving targets represent a major challenge. By monitoring a moving target it is possible to make the beam follow the motion, shaped by a Dynamic MLC (DMLC). The aim of this work was to evaluate the dose delivered to moving targets using the RapidArc (Varian Medical Systems, Inc.) technology with and without a DMLC tracking algorithm. MATERIAL AND METHODS: A Varian Clinac iX was equipped with a preclinical RapidArc and a 3D DMLC tracking application. A motion platform was placed on the couch, with the detectors on top: a PTW seven29 and a Scandidos Delta4. One lung plan and one prostate plan were delivered. Motion was monitored using a Real-time Position Management (RPM) system. Reference measurements were performed for both plans with both detectors at state (0) "static, no tracking". Comparing measurements were made at state (1) "motion, no tracking" and state (2) "motion, tracking". RESULTS: Gamma analysis showed a significant improvement from measurements of state (1) to measurements of state (2) compared to the state (0) measurements: Lung plan; from 87 to 97% pass. Prostate plan; from 81 to 88% pass. Sub-beam information gave a much reduced pattern of periodically spatial deviating dose points for state (2) than for state (1). Iso-dose curve comparisons showed a slightly better agreement between state (0) and state (2) than between state (0) and state (1). CONCLUSIONS: DMLC tracking together with RapidArc make a feasible combination and is capable of improving the dose distribution delivered to a moving target. It seems to be of importance to minimize noise influencing the tracking, to gain the full benefit from the application.

Comparison of CT-number parameterization models for stoichiometric CT calibration in proton therapy.

PURPOSE: This study compares the predictions of three parameterization models used in previously published works, implementing the stoichiometric CT calibration for proton therapy, and a further two alternative parameterizations suggested here. METHODS: Stoichiometric calibrations of patient CT-number to stopping-power ratio (SPR) were performed for four CT protocols using tissue substitutes supplied by CIRS (CIRS Inc., Norfolk, VA, USA). To evaluate robustness of the five models (Sch96/Sch00/Mar12/Karol/Spek), the calibration was repeatedly simulated by randomly perturbing the measured CT-numbers of the tissue substitutes (1σ:10 HU). The impact of high-Z content was assessed through calibrations where the two substitutes with barium content were replaced by hypothetical materials without barium. RESULTS: The stoichiometric calibrations generally agreed within 1% between the models, for non-bony tissues. For higher CT-numbers, a well-known 2-parameter model (Sch00) generated larger SPRs compared to the other models, with inter-model discrepancies of up to 3%. The 95% coverage interval of the calibrations obtained from the robustness analysis varied substantially. The well-known 2- and 3-parameter models (Sch00/Sch96) had the largest intervals. However, the partly-hypothetical (i.e. no barium) input data generated calibrations that agreed within 1% over the whole CT scale for all models and improved the 95% coverage interval of the well-known models (Sch00/Sch96). CONCLUSION: All parameterization models performed comparably if the scanned materials only contained elements with Z ≤ 20. However, the two alternative models proposed here (Karol/Spek), together with a previously published 1-parameter model (Mar12), generated robust calibrations in close agreement even when tissue substitutes contain elements with higher atomic number.

Technical Note: On the calculation of stopping-power ratio for stoichiometric calibration in proton therapy.

PURPOSE: The quantitative effects of assumptions made in the calculation of stopping-power ratios (SPRs) are investigated, for stoichiometric CT calibration in proton therapy. The assumptions investigated include the use of the Bethe formula without correction terms, Bragg additivity, the choice of I-value for water, and the data source for elemental I-values. METHODS: The predictions of the Bethe formula for SPR (no correction terms) were validated against more sophisticated calculations using the SRIM software package for 72 human tissues. A stoichiometric calibration was then performed at our hospital. SPR was calculated for the human tissues using either the assumption of simple Bragg additivity or the Seltzer-Berger rule (as used in ICRU Reports 37 and 49). In each case, the calculation was performed twice: First, by assuming the I-value of water was an experimentally based value of 78 eV (value proposed in Errata and Addenda for ICRU Report 73) and second, by recalculating the I-value theoretically. The discrepancy between predictions using ICRU elemental I-values and the commonly used tables of Janni was also investigated. RESULTS: Errors due to neglecting the correction terms to the Bethe formula were calculated at less than 0.1% for biological tissues. Discrepancies greater than 1%, however, were estimated due to departures from simple Bragg additivity when a fixed I-value for water was imposed. When the I-value for water was calculated in a consistent manner to that for tissue, this disagreement was substantially reduced. The difference between SPR predictions when using Janni's or ICRU tables for I-values was up to 1.6%. Experimental data used for materials of relevance to proton therapy suggest that the ICRU-derived values provide somewhat more accurate results (root-mean-square-error: 0.8% versus 1.6%). CONCLUSIONS: The conclusions from this study are that (1) the Bethe formula can be safely used for SPR calculations without correction terms; (2) simple Bragg additivity can be reasonably assumed for compound materials; (3) if simple Bragg additivity is assumed, then the I-value for water should be calculated in a consistent manner to that of the tissue of interest (rather than using an experimentally derived value); (4) the ICRU Report 37 I-values may provide a better agreement with experiment than Janni's tables.

Real-time dynamic MLC tracking for inversely optimized arc radiotherapy.

BACKGROUND AND PURPOSE: Motion compensation with MLC tracking was tested for inversely optimized arc radiotherapy with special attention to the impact of the size of the target displacements and the angle of the leaf trajectory. MATERIALS AND METHODS: An MLC-tracking algorithm was used to adjust the MLC positions according to the target movements using information from an optical real-time positioning management system. Two plans with collimator angles of 45 degrees and 90 degrees , respectively, were delivered and measured using the Delta(4)(R) dosimetric device moving in the superior-inferior direction with peak-to-peak displacements of 5, 10, 15, 20 and 25 mm and a cycle time of 6s. RESULTS: Gamma index evaluation for plan delivery with MLC tracking gave a pass rate higher than 98% for criteria 3% and 3 mm for both plans and for all sizes of the target displacement. With no motion compensation, the average pass rate was 75% for plan 1 and 70% for plan 2 for 25 mm peak-to-peak displacement. CONCLUSION: MLC tracking improves the accuracy of inversely optimized arc delivery for the cases studied. With MLC tracking, the dosimetric accuracy was independent of the magnitude of the peak-to-peak displacement of the target and not significantly affected by the angle between the leaf trajectory and the target movements.