Adaptation Time as a Determinant of the Dosimetric Effectiveness of Online Adaptive Radiotherapy for Bladder Cancer.

Interfraction anatomic deformations decrease the precision of radiotherapy, which can be improved by online adaptive radiation therapy (oART). However, oART takes time, allowing intrafractional deformations. In this study on focal radiotherapy for bladder cancer, we analyzed the time effect of oART on the equivalent uniform dose in the CTV (EUDCTV) per fraction and for the accumulated dose distribution over a treatment series as measure of effectiveness. A time-dependent digital CTV model was built from deformable image registration (DIR) between pre- and post-adaptation imaging. The model was highly dose fraction-specific. Planning target volume (PTV) margins were varied by shrinking the clinical PTV to obtain the margin-specific CTV. The EUDCTV per fraction decreased by-4.4 ± 0.9% of prescribed dose per min in treatment series with a steeper than average time dependency of EUDCTV. The EUDCTV for DIR-based accumulated dose distributions over a treatment series was significantly dependent on adaptation time and PTV margin (p < 0.0001, Chi2 test for each variable). Increasing adaptation times larger than 10 min by five minutes requires a 1.9 ± 0.24 mm additional margin to maintain EUDCTV for a treatment series. Adaptation time is an important determinant of the precision of oART for one half of the bladder cancer patients, and it should be aimed at to be minimized.

Long-Term Follow-Up of Patients with Conjunctival Lymphoma after Individualized Lens-Sparing Electron Radiotherapy: Results from a Longitudinal Study.

Irradiation with electrons is the primary treatment regime for localized conjunctival low-grade lymphomas. However, radiation-induced cataracts are a major cause of treatment-related morbidity. This study investigates whether lens-sparing electron irradiation produces sufficient disease control rates while preventing cataract formation. All consecutive patients with strictly conjunctival, low-grade Ann Arbor stage IE lymphoma treated with superficial electron irradiation between 1999 and 2021 at our department were reviewed. A total of 56 patients with 65 treated eyes were enrolled with a median follow-up of 65 months. The median dose was 30.96 Gy. A lens-spearing technique featuring a hanging rod blocking the central beam axis was used in 89.2% of all cases. Cumulative incidences of 5- and 10-year infield recurrences were 4.3% and 14.6%, incidences of 5- and 10-year outfield progression were 10.4% and 13.4%. We used patients with involvement of retroorbital structures treated with whole-orbit photon irradiation without lens protection-of which we reported in a previous study-as a control group. The cumulative cataract incidence for patients treated with electrons and lens protection was significantly lower (p = 0.005) when compared to patients irradiated without lens protection. Thus, electrons are an effective treatment option for conjunctival low-grade lymphomas. The presented lens-sparing technique effectively prevents cataract formation.

Fractionation versus Adaptation for Compensation of Target Volume Changes during Online Adaptive Radiotherapy for Bladder Cancer: Answers from a Prospective Registry.

Online adaptive radiotherapy (ART) allows adaptation of the dose distribution to the anatomy captured by with pre-adaptation imaging. ART is time-consuming, and thus intra-fractional deformations can occur. This prospective registry study analyzed the effects of intra-fraction deformations of clinical target volume (CTV) on the equivalent uniform dose (EUDCTV) of focal bladder cancer radiotherapy. Using margins of 5-10 mm around CTV on pre-adaptation imaging, intra-fraction CTV-deformations found in a second imaging study reduced the 10th percentile of EUDCTV values per fraction from 101.1% to 63.2% of the prescribed dose. Dose accumulation across fractions of a series was determined with deformable-image registration and worst-case dose accumulation that maximizes the correlation of cold spots. A strong fractionation effect was demonstrated-the EUDCTV was above 95% and 92.5% as determined by the two abovementioned accumulation methods, respectively, for all series of dose fractions. A comparison of both methods showed that the fractionation effect caused the EUDCTV of a series to be insensitive to EUDCTV-declines per dose fraction, and this could be explained by the small size and spatial variations of cold spots. Therefore, ART for each dose fraction is unnecessary, and selective ART for fractions with large inter-fractional deformations alone is sufficient for maintaining a high EUDCTV for a radiotherapy series.

Comparison of Online-Onboard Adaptive Intensity-Modulated Radiation Therapy or Volumetric-Modulated Arc Radiotherapy With Image-Guided Radiotherapy for Patients With Gynecologic Tumors in Dependence on Fractionation and the Planning Target Volume Margin.

Importance: Patients with newly diagnosed locally advanced cervical carcinomas or recurrences after surgery undergoing radiochemotherapy whose tumor is unsuited for a brachytherapy boost need high-dose percutaneous radiotherapy with small margins to compensate for clinical target volume deformations and set-up errors. Cone-beam computed tomography-based online adaptive radiotherapy (ART) has the potential to reduce planning target volume (PTV) margins below 5 mm for these tumors. Objective: To compare online ART technologies with image-guided radiotherapy (IGRT) for gynecologic tumors. Design, Setting, and Participants: This comparative effectiveness study comprised all 7 consecutive patients with gynecologic tumors who were treated with ART with artificial intelligence segmentation from January to May 2022 at the West German Cancer Center. All adapted treatment plans were reviewed for the new scenario of organs at risk and target volume. Dose distributions of adapted and scheduled plans optimized on the initial planning computed tomography scan were compared. Exposure: Online ART for gynecologic tumors. Main Outcomes and Measures: Target dose coverage with ART compared with IGRT for PTV margins of 5 mm or less in terms of the generalized equivalent uniform dose (gEUD) without increasing the gEUD for the organs at risk (bladder and rectum). Results: The first 10 treatment series among 7 patients (mean [SD] age, 65.7 [16.5] years) with gynecologic tumors from a prospective observational trial performed with ART were compared with IGRT. For a clinical PTV margin of 5 mm, IGRT was associated with a median gEUD decrease in the interfractional clinical target volume of -1.5% (90% CI, -31.8% to 2.9%) for all fractions in comparison with the planned dose distribution. Online ART was associated with a decrease of -0.02% (90% CI, -3.2% to 1.5%), which was less than the decrease with IGRT (P < .001). This was not associated with an increase in the gEUD for the bladder or rectum. For a PTV margin of 0 mm, the median gEUD deviation with IGRT was -13.1% (90% CI, -47.9% to 1.6%) compared with 0.1% (90% CI, -2.3% to 6.6%) with ART (P < .001). The benefit associated with ART was larger for a PTV margin of 0 mm than of 5 mm (P = .004) due to spreading of the cold spot at the clinical target volume margin from fraction to fraction with a median SD of 2.4 cm (90% CI, 1.9-3.4 cm) for all patients. Conclusions and Relevance: This study suggests that ART is associated with an improvement in the percentage deviation of gEUD for the interfractional clinical target volume compared with IGRT. As the gain of ART depends on fractionation and PTV margin, a strategy is proposed here to switch from IGRT to ART, if the delivered gEUD distribution becomes unfavorable in comparison with the expected distribution during the course of treatment.

Machine-learning-based prediction of the effectiveness of the delivered dose by exhale-gated radiotherapy for locally advanced lung cancer: The additional value of geometric over dosimetric parameters alone.

Purpose: This study aimed to assess interfraction stability of the delivered dose distribution by exhale-gated volumetric modulated arc therapy (VMAT) or intensity-modulated arc therapy (IMAT) for lung cancer and to determine dominant prognostic dosimetric and geometric factors. Methods: Clinical target volume (CTVPlan) from the planning CT was deformed to the exhale-gated daily CBCT scans to determine CTVi, treated by the respective dose fraction. The equivalent uniform dose of the CTVi was determined by the power law (gEUDi) and cell survival model (EUDiSF) as effectiveness measure for the delivered dose distribution. The following prognostic factors were analyzed: (I) minimum dose within the CTVi (Dmin_i), (II) Hausdorff distance (HDDi) between CTVi and CTVPlan, (III) doses and deformations at the point in CTVPlan at which the global minimum dose over all fractions per patient occurs (PDmin_global_i), and (IV) deformations at the point over all CTVi margins per patient with the largest Hausdorff distance (HDPworst). Prognostic value and generalizability of the prognostic factors were examined using cross-validated random forest or multilayer perceptron neural network (MLP) classifiers. Dose accumulation was performed using back deformation of the dose distribution from CTVi to CTVPlan. Results: Altogether, 218 dose fractions (10 patients) were evaluated. There was a significant interpatient heterogeneity between the distributions of the normalized gEUDi values (p<0.0001, Kruskal-Wallis tests). Accumulated gEUD over all fractions per patient was 1.004-1.023 times of the prescribed dose. Accumulation led to tolerance of ~20% of fractions with gEUDi <93% of the prescribed dose. Normalized Dmin >60% was associated with predicted gEUD values above 95%. Dmin had the highest importance for predicting the gEUD over all analyzed prognostic parameters by out-of-bag loss reduction using the random forest procedure. Cross-validated random forest classifier based on Dmin as the sole input had the largest Pearson correlation coefficient (R=0.897) in comparison to classifiers using additional input variables. The neural network performed better than the random forest classifier, and the gEUD values predicted by the MLP classifier with Dmin as the sole input were correlated with the gEUD values characterized by R=0.933 (95% CI, 0.913-0.948). The performance of the full MLP model with all geometric input parameters was slightly better (R=0.952) than that based on Dmin (p=0.0034, Z-test). Conclusion: Accumulated dose distributions over the treatment series were robust against interfraction CTV deformations using exhale gating and online image guidance. Dmin was the most important parameter for gEUD prediction for a single fraction. All other parameters did not lead to a markedly improved generalizable prediction. Dosimetric information, especially location and value of Dmin within the CTV i , are vital information for image-guided radiation treatment.

Validation of new 2D ripple filters in proton treatments of spherical geometries and non-small cell lung carcinoma cases.

A ripple filter (RiFi) is a passive energy modulator used in scanned particle therapy to broaden the Bragg peak, thus lowering the number of accelerator energies required for homogeneous target coverage, which significantly reduces the irradiation time. As we have previously shown, a new 6 mm thick RiFi with 2D groove shapes produced with 3D printing can be used in carbon ion treatments with a similar target coverage and only a marginally worse planning conformity compared to treatments with in-use 3 mm thick RiFis of an older 1D design. Where RiFis are normally not used with protons due to larger scattering and straggling effects, this new design would be beneficial in proton therapy too. Measurements of proton Bragg curves and lateral beam profiles were carried out for different RiFi designs and thicknesses as well as for no RiFi at the Heidelberg Ionenstrahl-Therapiezentrum. Base data for proton treatment planning were generated with the Monte Carlo code SHIELD-HIT12A with and without the 2D 6 mm RiFi. Plans on spherical targets in water were calculated with TRiP98 for a systematic RiFi performance analysis and for comparisons with carbon ion plans for the same respective energy depth step sizes. Plans for 9 stage I static non small cell lung cancer patients were calculated with Eclipse 13.7.15. Dose-volume-histograms, spatial dose distributions and dosimetric indexes were used for plan evaluation. Measurements confirm the functionality of the new 2D RiFi design, which reduces the beam spot size compared to 1D RiFis of the same thickness. Planning studies show that a 6 mm thick 2D RiFi could be used in proton therapy to lower the irradiation time. Although slightly worse planning conformity and dose homogeneity were found for plans with the RiFi compared to plans without, satisfactory results within the planning objective were obtained for all cases.

3D range-modulator for scanned particle therapy: development, Monte Carlo simulations and experimental evaluation.

The purpose of this work was to design and manufacture a 3D range-modulator for scanned particle therapy. The modulator is intended to create a highly conformal dose distribution with only one fixed energy, simultaneously reducing considerably the treatment time. As a proof of concept, a 3D range-modulator was developed for a spherical target volume with a diameter of 5 cm, placed at a depth of 25 cm in a water phantom. It consists of a large number of thin pins with a well-defined shape and different lengths to modulate the necessary shift of the Bragg peak. The 3D range-modulator was manufactured with a rapid prototyping technique. The FLUKA Monte Carlo package was used to simulate the modulating effect of the 3D range-modulator and the resulting dose distribution. For that purpose, a special user routine was implemented to handle its complex geometrical contour. Additionally, FLUKA was extended with the capability of intensity modulated scanning. To validate the simulation results, dose measurements were carried out at the Heidelberg Ion Beam Therapy Center with a 400.41 MeV/u 12C beam. The high resolution dosimetric measurements show a good agreement between simulated and measured dose distributions. Irradiation of the monoenergetic raster plan took 3 s, which is approximately 20 times shorter than a comparable plan with 16 different energies. The combination of only one energy and a 3D range-modulator leads to a tremendous decrease in irradiation time. 'Interplay effects', typical for moving targets and pencil beam scanning, can be immensely reduced or disappear completely, making the delivery of a homogeneous dose to moving targets more reliable. Combining high dose conformity, very good homogeneity and extremely short irradiation times, the 3D range-modulator is considered to become a clinically applicable method for very fast treatment of lung tumours.

Modulation power of porous materials and usage as ripple filter in particle therapy.

Porous materials with microscopic structures like foam, sponges, lung tissues and lung substitute materials have particular characteristics, which differ from those of solid materials. Ion beams passing through porous materials show much stronger energy straggling than expected for non-porous solid materials of the same thickness. This effect depends on the microscopic fine structure, the density and the thickness of the porous material. The beam-modulating effect from a porous plate enlarges the Bragg peak, yielding similar benefits in irradiation time reduction as a ripple filter. A porous plate can additionally function as a range shifter, which since a higher energy can be selected for the same penetration depth in the body reduces the scattering at the beam line and therefore improves the lateral fall-off. Bragg curve measurements of ion beams passing through different porous materials have been performed in order to determine the beam modulation effect of each. A mathematical model describing the correlation between the mean material density, the porous pore structure size and the strength of the modulation has been developed and a new material parameter called 'modulation power' is defined as the square of the Gaussian sigma divided by the mean water-equivalent thickness of the porous absorber. Monte Carlo simulations have been performed in order to validate the model and to investigate the Bragg peak enlargement, the scattering effects of porosity and the lateral beam width at the end of the beam range. The porosity is found to only influence the lateral scattering in a negligible way. As an example of a practical application, it is found that a 20 mm and 50 mm plate of Gammex LN300 performs similar to a 3 mm and 6 mm ripple filter, respectively, and at the same time can improve the sharpness of the lateral beam due to its multifunctionality as a ripple filter and a range shifter.

Dosimetric comparisons of carbon ion treatment plans for 1D and 2D ripple filters with variable thicknesses.

A ripple filter (RiFi)-also called mini-ridge filter-is a passive energy modulator used in particle beam treatments that broadens the Bragg peak (BP) as a function of its maximum thickness. The number of different energies requested from the accelerator can thus be reduced, which significantly reduces the treatment time. A new second generation RiFi with 2D groove shapes was developed using rapid prototyping, which optimizes the beam-modulating material and enables RiFi thicknesses of up to 6 mm. Carbon ion treatment plans were calculated using the standard 1D 3 mm thick RiFi and the new 4 and 6 mm 2D RiFis for spherical planning target volumes (PTVs) in water, eight stage I non-small cell lung cancer cases, four skull base chordoma cases and three prostate cancer cases. TRiP98 was used for treatment planning with facility-specific base data calculated with the Monte Carlo code SHIELD-HIT12A. Dose-volume-histograms, spatial dose distributions and dosimetric indexes were used for plan evaluation. Plan homogeneity and conformity of thinner RiFis were slightly superior to thicker RiFis but satisfactory results were obtained for all RiFis investigated. For the 6 mm RiFi, fine structures in the dose distribution caused by the larger energy steps were observed at the PTV edges, in particular for superficial and/or very small PTVs but performances for all RiFis increased with penetration depth due to straggling and scattering effects. Plans with the new RiFi design yielded for the studied cases comparable dosimetric results to the standard RiFi while the 4 and 6 mm RiFis lowered the irradiation time by 25-30% and 45-49%, respectively.

Fluence inhomogeneities due to a ripple filter induced Moiré effect.

At particle therapy facilities with pencil beam scanning, the implementation of a ripple filter (RiFi) broadens the Bragg peak, so fewer energy steps from the accelerator are required for a homogeneous dose coverage of the planning target volume (PTV). However, sharply focusing the scanned pencil beams at the RiFi plane by ion optical settings can lead to a Moiré effect, causing fluence inhomogeneities at the isocenter. This has been experimentally proven at the Heidelberg Ionenstrahl-Therapiezentrum (HIT), Universitätsklinikum Heidelberg, Germany. 150 MeV u(-1) carbon-12 ions are used for irradiation with a 3 mm thick RiFi. The beam is focused in front of and as close to the RiFi plane as possible. The pencil beam width is estimated to be 0.78 mm at a 93 mm distance from the RiFi. Radiographic films are used to obtain the fluence profile 30 mm in front of the isocenter, 930 mm from the RiFi. The Monte Carlo (MC) code SHIELD-HIT12A is used to determine the RiFi-induced inhomogeneities in the fluence distribution at the isocenter for a similar setup, pencil beam widths at the RiFi plane ranging from σχ(RiFi to 1.2 mm and for scanning step sizes ranging from 1.5 to 3.7 mm. The beam application and monitoring system (BAMS) used at HIT is modelled and simulated. When the width of the pencil beams at the RiFi plane is much smaller than the scanning step size, the resulting inhomogeneous fluence distribution at the RiFi plane interfers with the inhomogeneous RiFi mass distribution and fluence inhomogeneity can be observed at the isocenter as large as an 8% deviation from the mean fluence. The inverse of the fluence ripple period at the isocenter is found to be the difference between the inverse of the RiFi period and the inverse of the scanning step size. We have been able to use MC simulations to reproduce the spacing of the ripple stripes seen in films irradiated at HIT. Our findings clearly indicate that pencil beams sharply focused near the RiFi plane result in fluence inhomogeneity at the isocenter. In the normal clinical application, such a setting should generally be avoided.

Monte Carlo simulations of new 2D ripple filters for particle therapy facilities.

UNLABELLED: At particle therapy facilities with pencil beam scanning, the implementation of a ripple filter (RiFi) broadens the Bragg peak (BP), which leads to fewer energy steps from the accelerator required to obtain an homogeneous dose coverage of the planned target volume (PTV). At the Universitätsklinikum Gießen und Marburg, Germany, a new second generation RiFi has been developed with two-dimensional groove structures. In this work we evaluate this new RiFi design. METHODS: The Monte Carlo (MC) code SHIELD-HIT12A is used to determine the RiFi-induced inhomogeneities in the dose distribution for various ion types, initial particle energies and distances from the RiFi to the phantom surface as well as in the depth of the phantom. The beam delivery and monitor system (BAMS) used at Marburg, the Heidelberg Ionentherapiezentrum (HIT), Universitätsklinikum Heidelberg, Germany and the GSI Helmholtzzentrum für Schwerionenforschung, Darmstadt, Germany is modeled and simulated. To evaluate the PTV dose coverage performance of the new RiFi design, the heavy ion treatment planning system TRiP98 is used for dose optimization. SHIELD-HIT12A is used to prepare the facility-specific physical dose kernels needed by TRiP, and for recalculating the physical dose distribution after TRiP optimization. RESULTS: At short distances from the RiFi to the phantom surface fine structures in the dose distribution are observed. For various RiFis, ion types and initial particle energies the distance dmax at which maximum dose inhomogeneity occurs is found and an expression for dmax is deduced. The distance d0.01 at which the dose inhomogeneity is less than 1% is estimated and used as a threshold distance at which dose distributions are considered homogeneous. The MC data are found to agree with analytical expressions for dmax and d0.01; both are inversely related to the angular distribution. Increasing scatter from the beam delivery and monitoring system results in reduced dmax and d0.01. Furthermore, dmax and d0.01 are found to be proportional to the RiFi period λ. CONCLUSION: Our findings clearly indicate that the dose inhomogeneity induced by RiFis does not add uncertainties to the dose distribution in the clinical setting. The new RiFi design can be used in treatments to obtain homogeneous PTV dose coverage with fewer energy steps while improving lateral penumbra, thereby reducing the required treatment time.