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.

Experimental Examination of Conventional, Semi-Automatic, and Automatic Volumetry Tools for Segmentation of Pulmonary Nodules in a Phantom Study.

The aim of this study is to examine the precision of semi-automatic, conventional and automatic volumetry tools for pulmonary nodules in chest CT with phantom N1 LUNGMAN. The phantom is a life-size anatomical chest model with pulmonary nodules representing solid and subsolid metastases. Gross tumor volumes (GTVis) were contoured using various approaches: manually (0); as a means of semi-automated, conventional contouring with (I) adaptive-brush function; (II) flood-fill function; and (III) image-thresholding function. Furthermore, a deep-learning algorithm for automatic contouring was applied (IV). An intermodality comparison of the above-mentioned strategies for contouring GTVis was performed. For the mean GTVref (standard deviation (SD)), the interquartile range (IQR)) was 0.68 mL (0.33; 0.34-1.1). GTV segmentation was distributed as follows: (I) 0.61 mL (0.27; 0.36-0.92); (II) 0.41 mL (0.28; 0.23-0.63); (III) 0.65 mL (0.35; 0.32-0.90); and (IV) 0.61 mL (0.29; 0.33-0.95). GTVref was found to be significantly correlated with GTVis (I) p < 0.001, r = 0.989 (III) p = 0.001, r = 0.916, and (IV) p < 0.001, r = 0.986, but not with (II) p = 0.091, r = 0.595. The Sørensen-Dice indices for the semi-automatic tools were 0.74 (I), 0.57 (II) and 0.71 (III). For the semi-automatic, conventional segmentation tools evaluated, the adaptive-brush function (I) performed closest to the reference standard (0). The automatic deep learning tool (IV) showed high performance for auto-segmentation and was close to the reference standard. For high precision radiation therapy, visual control, and, where necessary, manual correction, are mandatory for all evaluated tools.

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.

Photons, protons or carbon ions for stage I non-small cell lung cancer - Results of the multicentric ROCOCO in silico study.

PURPOSE: To compare dose to organs at risk (OARs) and dose-escalation possibility for 24 stage I non-small cell lung cancer (NSCLC) patients in a ROCOCO (Radiation Oncology Collaborative Comparison) trial. METHODS: For each patient, 3 photon plans [Intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT) and CyberKnife], a double scattered proton (DSP) and an intensity-modulated carbon-ion (IMIT) therapy plan were created. Dose prescription was 60 Gy (equivalent) in 8 fractions. RESULTS: The mean dose and dose to 2% of the clinical target volume (CTV) were lower for protons and ions compared with IMRT (p < 0.01). Doses to the lungs, heart, and mediastinal structures were lowest with IMIT (p < 0.01), doses to the spinal cord were lowest with DSP (p < 0.01). VMAT and CyberKnife allowed for reduced doses to most OARs compared with IMRT. Dose escalation was possible for 8 patients. Generally, the mediastinum was the primary dose-limiting organ. CONCLUSION: On average, the doses to the OARs were lowest using particles, with more homogenous CTV doses. Given the ability of VMAT and CyberKnife to limit doses to OARs compared with IMRT, the additional benefit of particles may only be clinically relevant in selected patients and thus should be carefully weighed for every individual patient.

Challenges in radiobiological modeling: can we decide between LQ and LQ-L models based on reviewed clinical NSCLC treatment outcome data?

AIM: To study the dose-response of stage I non-small-cell lung cancer (NSCLC) in terms of long-term local tumor control (LC) after conventional and hypofractionated photon radiotherapy, modeled with the linear-quadratic (LQ) and linear-quadratic-linear (LQ-L) approaches and to estimate the clinical α/ß ratio within the LQ frame. MATERIAL AND METHODS: We identified studies of curative radiotherapy as single treatment through MedLine search reporting 3-year LC as primary outcome of interest. Logistic models coupled with the biologically effective dose (BED) at isocenter and PTV edge according to both the LQ and LQ-L models with α/ß = 10 Gy were fitted. Additionally, α/ß was estimated from direct LQ fits. RESULTS: Thirty one studies were included reporting outcome of 2319 patients. The LQ-L fit yielded a significant value of 11.0 ± 5.2 Gy for the dose threshold (Dt) for BED10 at the isocenter. The LQ and LQ-L fits did not differ substantially. Concerning the estimation of α/ß, the value obtained from the direct LQ fit for the complete fractionation range was 3.9 [68 % CI: 2.2-9.0] Gy (p > 0.05). CONCLUSION: Both LQ and LQ-L fits can model local tumor control after conventionally and hypofractionated irradiation and are robust methods for predicting clinical effects. The observed dose-effect for local control in NSCLC is weaker at high doses due to data dispersion. For BED10 values of 100-150 Gy in ≥3 fractions, the differences in isoeffects predicted by both models can be neglected.

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.

Changes in the radiological depth correlate with dosimetric deterioration in particle therapy for stage I NSCLC patients under high frequency jet ventilation.

BACKGROUND: Particle dose distributions are highly sensitive to anatomy changes in the beam path, which may lead to substantial dosimetric deviations. Robust planning and dedicated image guidance together with strategies for online decision making to counteract dosimetric deterioration are thus mandatory. We aimed to develop methods to quantify anatomical discrepancies as depicted by repeated computed tomography (CT) imaging and to test whether they can predict deviations in target coverage. MATERIAL AND METHODS: Dedicated software tools allowed for voxel-based calculations of changes in the water equivalent path length (WEPL) in beam directions. We prepared proton and carbon ion plans with different coplanar beam angle settings on a series of lung cancer patients, for which planning and localization CT scans under high frequency jet ventilation (HFJV) for tumor fixation were performed. We investigated the reproducibility of target coverage between the optimized and recalculated treatment plans. We then studied how different raster scan and planning settings influence the robustness. Finally, we carried out a systematic analysis of the variations in the WEPL along different coplanar beam angles to find beam directions, which could minimize such variations. RESULTS: The Spearman's correlations for the GTV ΔV95 and ΔV98 with the ΔWEPL for the proton plans with a 0° and -45° two-field configuration were 0.701 (p = 0.02) and 0.719 (p = 0.08), respectively. For beam configurations 0° and -90°, or 0° and + 45°, with lower ΔWEPL, the correlations were no significant. The same trends were observed for the carbon ion plans. Increased beam spot overlap reduced dosimetric deterioration in case of large ΔWEPL. CONCLUSION: Software tools for fast online analysis of WEPL changes might help supporting clinical decision making of image guidance. Raster scan and treatment planning settings can help to compensate for anatomical deviations.

Imaging dose assessment for IGRT in particle beam therapy.

INTRODUCTION: Image-guided advanced photon and particle beam treatments are promising options for improving lung treatments. Extensive use of imaging increases the overall patient dose. The aim of this study was to determine the imaging dose for different IGRT solutions used in photon and particle beam therapy. MATERIAL AND METHODS: Measurements were performed in an Alderson phantom with TLDs. Clinically applied protocols for orthogonal planar kV imaging, stereoscopic imaging, CT scout views, fluoroscopy, CT, 4D-CT and CBCT were investigated at five ion beam centers and one conventional radiotherapy department. The overall imaging dose was determined for a patient undergoing a lung tumor irradiation with institute specific protocols. RESULTS: OAR doses depended on imaging modality and OAR position. Dose values were in the order of 1 mGy for planar and stereoscopic imaging and 10-50 mGy for volumetric imaging, except for one CBCT device leading to lower doses. The highest dose per exam (up to 150 mGy to the skin) was recorded for a 3-min fluoroscopy. DISCUSSION: Modalities like planar kV or stereoscopic imaging result in very low doses (≈ 1 mGy) to the patient. Imaging a moving target during irradiation, low-dose protocols and protocol optimization can reduce the imaging dose to the patient substantially.

Reproducibility of target coverage in stereotactic spot scanning proton lung irradiation under high frequency jet ventilation.

PURPOSE: To investigate scanned-beam proton dose distribution reproducibility in the lung under high frequency jet ventilation (HFJV). MATERIALS AND METHODS: For 11 patients (12 lesions), treated with single-fraction photon stereotactic radiosurgery under HFJV, scanned-beam proton plans were prepared with the TRiP98 treatment planning system using 2, 3-4 and 5-7 beams. The planning objective was to deliver at least 95% of the prescription of 33 Gy (RBE) to 98% of the PTV. Plans were subsequently recomputed on localization CT scans. Additionally, for selected cases, the effects of range uncertainties were investigated. RESULTS: Median GTV V(98%) was 98.7% in the original 2-field plans and 93.7% in their recomputation (p=0.039). The respective values were 99.0% and 98.0% (p=0.039) for the 3-4-field plans and 100.0% and 99.6% (p=0.125) for the 5-7-field plans. CT calibration uncertainties of ±3.5% led to a GTV V(98%) reduction below 1.5 percentual points in most cases and reaching 3 percentual points for 2-field plans with beam undershoot. CONCLUSIONS: Through jet ventilation, reproducible tumor fixation for proton radiotherapy of lung lesions is achievable, ensuring excellent target coverage in most cases. In few cases, non-optimal patient setup reproducibility induced density changes across beam entrance channels, leading to dosimetric deterioration between planning and delivery.

Effect of cetuximab and fractionated irradiation on tumour micro-environment.

BACKGROUND AND PURPOSE: Previous experiments have shown that application of the anti-EGFR monoclonal antibody C225 (cetuximab) improves local tumour control after irradiation in FaDu human squamous cell carcinoma (hSCC) due to the combined effect of decreased repopulation and improved reoxygenation. The present study investigates early changes of the pimonidazole hypoxic fraction of FaDu tumours and the expression and phosphorylation of the EGFR and its downstream signal transduction molecules after treatment with C225 alone or in combination with irradiation. MATERIAL AND METHODS: FaDu tumour xenografts were irradiated with up to 3×3Gy with or without additional C225 treatment and excised at different time points. Tumour hypoxia was evaluated using pimonidazole. EGFR expression and phosphorylation and intratumoural distribution of C225 were assessed by immunofluorescence analysis. Western blots were performed to evaluate expression and phosphorylation of EGFR, ErbB2, AKT and MAPK (ERK1/2). RESULTS: Hypoxia did not change during the 4days of treatment in the tumours treated with C225 alone or combined with irradiation. C225 treatment led to downregulation of the total EGFR in FaDu tumours, accompanied by a change of the spatial distribution of the receptor favouring the membranous expression. An induction of phosphorylation of the EGFR (tyr992, tyr1173) was observed with C225 alone or combined with irradiation. AKT phosphorylation was decreased, whereas MAPK phosphorylation remained unchanged. C225 membrane staining was homogeneously distributed over the whole tumour with no differences between hypoxic and non-hypoxic tumour cells. CONCLUSION: Pimonidazole-hypoxia of FaDu tumours during the initial part of fractionated irradiation is not influenced by C225, indicating that external hypoxia markers may not be promising as biomarkers for tumour response to combined treatment. The downregulation of the total EGFR, but at the same time higher membrane staining, as well as the changes in downstream signal transduction molecules, warrants further investigation in other tumour models.

Comparison of [18F]FDG uptake and distribution with hypoxia and proliferation in FaDu human squamous cell carcinoma (hSCC) xenografts after single dose irradiation.

PURPOSE: This study investigated the uptake of [(18)F]2-fluoro-2-deoxy-glucose ([(18)F]FDG) in the human tumour xenograft FaDu at early time points after single dose irradiation with Positron-Emission-Tomography (PET), autoradiography and functional histology. MATERIALS AND METHODS: [(18)F]FDG-PET of FaDu hSCC xenografts on nude mice was performed before 25 Gy or 35 Gy single dose irradiation and one, seven or 11 days post irradiation (p.irr.). Before the second PET, mice were injected with pimonidazole (pimo) and bromodeoxyuridine (BrdU). After the PET tumours were excised, sliced and subjected to autoradiography and functional histology staining (pimo, BrdU, Ki67). [(18)F]FDG tumour uptake was quantified in the PET scans by maximal standard uptake value (SUV(max)) and in the autoradiography after co-registration to the histology slices. RESULTS: No differences in the overall [(18)F]FDG uptake between the two dose groups and time points were found with PET or autoradiography. Comparing autoradiography and histology, the [(18)F]FDG uptake was constant in tumour necrosis over time, while it decreased in vital tumour areas and particularly in hypoxic regions. No differences in the [(18)F]FDG uptake between positive and negative areas of Ki67 and BrdU were found. CONCLUSIONS: The decline of [(18)F]FDG uptake in vital tumour and in pimopositive areas as seen in autoradiography, was not reflected by evaluation of SUV(max) determined by PET. These findings suggest that the SUV(max) does not necessarily reflect changes in tumour biology after irradiation.