Nika Guberina

Background: In the online adaptive platform, a linear Boltzmann‐transport‐equation‐solver (LBTE) as calculation algorithm is implemented for dose optimization. This class‐C‐optimizer is known to counteract the dose decrease at boundaries of small fields due to electronic disequilibrium by increasing the fluence to achieve the goals of dose homogeneity within the PTV. Purpose: To analyze the dosimetric sensitivity of adaptive treatment plans for prostate cancer to intrafractional anatomic changes in the presence of rectal air using a CBCT‐based adaptive platform. Methods: In the first part of the study planning CT scans (CT _plan ) from eight patients treated with an air‐filled endorectal balloon and two patients presenting larger rectal air pockets were included in a simulation study. The dataset was used to assess the sensitivity of LBTE‐optimized treatment plans to intrafractional density variations and to changes in the overlap between the planning target volume (PTV) and an air cavity (PTV∩Air structure). Density changes resulting from anatomical shifts were simulated using water overrides (WOR) in defined shift regions within the PTV∩Air structure. These shift regions were created by dorsally expanding the clinical target volume (CTV) by margins of 2 mm or 5 mm. Additionally, a WOR of the entire rectum was applied. For each WOR scenario, D _max , D ₁ and D _1cc values were recorded within the fixed PTV∩Air structure and within the rectal wall, which was shifted according to the applied margin. A mixed linear model was built to describe dosimetric characteristics in dependence of the WOR scenario. Additionally, intrafractional variations of D _max within the PTV were assessed in 101 dose fractions from 15 patients who were treated with a rectal balloon and underwent online adaptive radiotherapy. All doses were normalized by the prescribed dose. Results: WOR within PTV∩Air‐structure overlap resulted in increases of the analyzed dosimetric characteristics. D _1cc increased with WOR within shift margins of 2 and 5 mm and within the entire rectal cavity by 2.2% ± 0.7%, 5.5% ± 0.7%, and 8.7% ± 1.0%, respectively ( p < 0.0001, F ‐test). The corresponding dose increases within the rectal wall were slightly smaller, with D _1cc increases of 1.4% ± 0.6%, 1.7% ± 0.9%, and 5.0% ± 0.5%. Sensitivity to WOR in the PTV∩Air using a 5 mm shift margin was markedly lower when the same treatment plans were recalculated with AAA compared with LBTE ( p  = 0.0020, signed‐rank test). On average, AAA detected only 43% ± 12% of the WOR effect predicted by LBTE. For prostate cancer patients treated with a rectal balloon, D _max , D ₁ and D _1cc changes in LBTE‐optimized plans showed 90% confidence intervals of [−0.05–0.05] due to intrafractional motion, suggesting that posterior tissue shifts of 5 mm or less do not have a clinically relevant impact. Conclusions: PTV∩Air larger than 5 mm led to LBTE‐optimized treatment plans, that are sensitive to anatomic soft tissue shifts larger than 5 mm in posterior direction with respect to dose homogeneity. PTV∩Air‐overlaps up to 5 mm led to LBTE‐optimized treatment plans, that showed only minor sensitivities to anatomic soft tissue shifts of 2–5 mm in posterior direction with respect to dose homogeneity. During online adaptive radiotherapy, the presence of rectal air pockets or an air‐filled rectal balloon did not result in clinically relevant dose increases, provided that intrafractional motion–induced soft tissue shifts remained within 5 mm in the posterior direction.

The impact of salvage radiotherapy (SRT) on overall survival (OS) in patients experiencing biochemical recurrence (BCR) of prostate cancer remains an area of active investigation. The international multicenter PROMISE registry provides a valuable dataset to explore the association between SRT and long-term clinical outcomes in this patient population (NCT06320223). Methods: Comprehensive restaging at the time of BCR was performed by integrating both serologic markers and advanced molecular imaging (PET/CT or PET/MRI), offering an accurate assessment of molecular imaging (mi) TNM stage. Results: In total, 1410 patients experiencing BCR with prior prostatectomy were included. The median follow-up was 5.2 y (interquartile range, 3.8-6.9 y). SRT was administered after PET to 381 of 680 patients (56.0%) with PET-negative disease (miT0N0M0) and to 478 of 730 patients (65.0%) with PET-locoregional disease (miT/N+ M0). SRT was associated with longer OS in the entire cohort (hazard ratio, 0.66; 95% CI, 0.47-0.93; P = 0.019) with 5- and 7-y survival rates of 95.2% (95% CI, 93.6%-96.8%) and 90.8% (95% CI, 88.1%-93.6%), respectively. Without SRT, 5- and 7-y survival rates were 92.1% (95% CI, 89.6%-94.7%) and 83.8% (95% CI, 79.8%-88.1%), respectively. Subgroup analysis found significant benefit for patients with miT0N0M0 disease (hazard ratio, 0.42; 95% CI, 0.22-0.78; P = 0.0061), particularly those with a prostate-specific antigen level of 0.5 ng/mL or lower (P = 0.03, log-rank test). Conclusion: SRT improves OS for patients with BCR, especially those with a negative prostate-specific membrane antigen-targeted PET.

Background/Objectives: Analysis of the density and spatial distribution of pulmonary infiltrates of patients with high-grade (≥3) pneumonitis after radiochemotherapy and durvalumab consolidation (RT/CTx + IO) was performed in order to define dosimetric hallmarks of the development of infiltrates following this multimodality treatment. Methods: Consecutive patients treated with RT/CTx + IO for stage III NSCLC were retrospectively reviewed with respect to the occurrence of grade ≥ 3 pneumonitis. Lung infiltrates were contoured on follow-up CT scans acquired around the time of maximum pneumonitis expression. The applied dose distribution was overlaid with the follow-up CT using elastic deformation, and infiltrates were binned according to their density in density strata of 50 HU. The dose and density dependence of partial infiltrate volumes per unit lung volume was analyzed using a mixed fixed and random effect model adjusting for patient, density and dose-dependent random effects. Results: Six patients with grade ≥ 3 pneumonitis were identified from 132 patients treated with RT/CT + IO at a comprehensive cancer center. Partial volumes of lung infiltrates captured by follow-up CT with maximum pneumonitis expression ranged from 15.5 to 60.0% (median 39.8%). A significant, systematic dose–response relationship was found for partial lung infiltrate volumes per dose and density bin. A unimodal density distribution of partial lung infiltrate volumes was also found over the infiltrate density range of −1000 to 100 HU. This was determined using a mixed model that adjusted for random effects (p < 0.0001 for both effects, F-test). There was no interaction effect between systematic dose and infiltrate density dependence of the partial infiltrate volumes. The proportion of infiltrate volumes that are attributable to the systematic dose–response relation amounts to a mean of 16.6% of the total infiltrate volume per patient according to this model. Compared to patients with pneumonitis of grade ≤ 2, patients with high-risk pneumonitis had higher partial infiltrate volumes, particularly in the low-dose regions in five grade dose bins up to 20 Gy (AUC = 1.0, p < 0.0001, likelihood-ratio test). Conclusions: Dose-dependent and -independent partial lung infiltrate volumes were found in patients with high-grade pneumonitis after RT/CTx + IO. These results indicate that pneumonitis involves contributions from both radiochemotherapy-induced and immunotherapy-related mechanisms.

Objective: Chest computed tomography (CT) is a key component of the diagnostic assessment of people with cystic fibrosis (PwCF) and is increasingly replacing chest radiography. Due to improvements in life expectancy, radiation exposure has become a growing concern in PwCF. Photon-counting CT (PCCT) has the potential to reduce the risk of radiation-induced malignancies while maintaining diagnostic accuracy. This study aimed to compare the radiation dose and image quality of low-dose high-resolution (LD-HR) and ultra-low-dose high-resolution (ULD-HR) CT protocols using PCCT in PwCF. Methods: This retrospective study included 72 PwCF, with 36 undergoing a LD-HR chest CT protocol and 36 receiving an ULD-HR protocol on a PCCT. The radiation dose and image quality were assessed by comparing the effective dose and signal-to-noise ratio (SNR). Three blinded radiologists evaluated the overall image quality, sharpness, noise, and assessability of the bronchi, bronchial wall thickening, and bronchiolitis using a five-point Likert scale. Results: The ULD-HR PCCT protocol reduced radiation exposure by approximately 65% compared with the LD-HR PCCT protocol (median effective dose: 0.19 vs. 0.55 mSv, p < 0.001). While LD-HR images were consistently rated higher than ULD-HR images (p < 0.001), both protocols maintained diagnostic significance (median image quality rating of “4-good”). The average SNR of the lung parenchyma was significantly lower with ULD-HR PCCT compared to LD-HR PCCT (p < 0.001). Conclusions: ULD-HR PCCT significantly reduced radiation exposure while maintaining good diagnostic image quality in PwCF. The effective dose of ULD-HR PCCT is only twice that of a two-plane chest X-ray, making it a viable low-radiation alternative for routine imaging in PwCF.

Background: Consolidation therapy with the anti-programmed death-ligand 1 (PD-L1) antibody durvalumab, or other immune checkpoint inhibitors, has been associated with improved progression-free and overall survival in patients with stage III non-small cell lung cancer (NSCLC) as demonstrated in randomized clinical trials. The purpose of the present study is to evaluate the dose-response relationship for partial lung infiltrate volumes per dose bin after definitive radiochemotherapy as a sensitive end point to detect a durvalumab effect on the lung parenchyma in patients with subclinical or grade ≤2 pneumonitis. Methods: Consecutive patients from a prospective registry with inoperable NSCLC stage III who developed no or pneumonitis grade ≤2 after definitive radiochemotherapy with or without durvalumab consolidation were included. Pulmonary infiltrates outside the planning target volumes were contoured in the follow-up computed tomography (CT) at the time of maximum infiltrate expression. Partial lung infiltrate volumes per dose bin were determined over the entire dose range. A mixed random and fixed effect model was used to fit dose response curves stepwise in dose bins of 5 Gy. The Akaike information criterion (AIC) was used for model comparison. Results: Sixty patients with and 44 without durvalumab consolidation were analysed. The step model showed a significant dose response relationship for the pulmonary infiltrates (PF-test) that was modified by the durvalumab effect (PF-test). There was a significant dependence of the durvalumab effect on radiation dose (P=0.003). The durvalumab effect increased with dose from 0% in the lowest dose bin as reference to 5.2%±1.2% partial lung infiltrate volume in the highest dose bin. There was significant inter-individual heterogeneity of partial lung infiltrate volumes at each dose bin (PF-test). The percentage of lung volume receiving at least 5 Gy (V5) was the most significant characteristic increasing risk of pulmonary infiltrates (PF-test). Multivariable proportional hazards Cox-model showed that pulmonary infiltrates at 5–10 and 35–40 Gy dose bins were dominant factors determining the risk of pneumonitis grade 2. Conclusions: The relationship between radiation dose and lung infiltrates observed by follow-up CT scans after radiochemotherapy is sensitive enough to detect factors that systematically increase the radiation dose response. In this case, the focus is on durvalumab consolidation and radiation dose to the lung. The dose-response relationship may help in the prediction of grade 2 pneumonitis. However, further research is needed to understand the biological factors that contribute to the large differences in response to radiation dose between individuals.

Background: In patients with oligometastatic NSCLC, a cT3–cT4 primary tumor or an cN2/cN3 lymph node status was reported to be associated with unfavorable outcome. The aim of this study was to assess the importance of definitive or neoadjuvant thoracic radiochemotherapy for long-term outcome of these patients in order to find more appropriate treatment schedules. Methods: Analysis of the West Cancer Centre (WTZ) institutional database from 08/2016 to 08/2020 was performed. Patients with primary synchronous OMD, all without actionable driver mutations, who received definitive thoracic radiochemotherapy (RCT) or neoadjuvant RCT followed by surgery (trimodality treatment) were included. Survival outcome is compared with stage III NSCLC. Results: Altogether, 272 patients received concurrent radiochemotherapy. Of those, 220 presented with stage III (158 with definitive RCT, 62 with trimodality approach). A total of 52 patients had OMD patients with cT3/cT4 or cN2/cN3 tumors. Overall survival (OS) at five years for OMD patients was 28.3% (95%-CI: 16.4–41.5%), which was not significantly different from OS of patients with stage III NSCLC treated with definitive or neoadjuvant RCT (34.9% (95%-CI: 27.4–42.8%)). However, the PFS of OMD patients at five years or last follow-up was significantly worse than that of stage III patients (13.0% vs. 24.3%, p = 0.0048). The latter was due to a higher cumulative incidence of distant metastases in OMD patients (50.2% vs. 20.4% at 48 months, p < 0.0001) in comparison to stage III patients. A cross-validated classifier that included severe comorbidity, ECOG performance status, gender and pre-treatment serum CRP level as the most important factors in the univariable analysis, was able to divide the OMD patient group into two equally sized groups with a four-year survival rate of 49.4% in the good prognosis group and 9.9% in the poor prognosis group (p = 0.0021). Laboratory chemistry and clinical parameters, in addition to imaging and high-precision therapies, can help to predict and improve prognosis. Conclusions: A multimodality treatment approach and local metastases-directed therapy in addition to chemoimmunotherapy can lead to good long-term survival in patients with cT3/cT4 or cN2/cN3 OMD NSCLC without severe comorbidities and in good performance status and is therefore recommended.

Background: The aim of the present study is to examine the impact of kV-CBCT-based online adaptive radiation therapy (ART) on dosimetric parameters in comparison to image-guided-radiotherapy (IGRT) in consecutive patients with tumors in the head and neck region from a prospective registry. Methods: The study comprises all consecutive patients with tumors in the head and neck area who were treated with kV-CBCT-based online ART or IGRT-modus at the linear-accelerator ETHOS™. As a measure of effectiveness, the equivalent-uniform-dose was calculated for the CTV (EUD_CTV) and organs-at-risk (EUD_OAR) and normalized to the prescribed dose. As an important determinant for the need of ART the interfractional shifts of anatomic landmarks related to the tongue were analyzed and compared to the intrafractional shifts. The latter determine the performance of the adapted dose distribution on the verification CBCT2 postadaptation. Results: Altogether 59 consecutive patients with tumors in the head-and-neck-area were treated from 01.12.2021 to 31.01.2023. Ten of all 59 patients (10/59; 16.9%) received at least one phase within a treatment course with ART. Of 46 fractions in the adaptive mode, irradiation was conducted in 65.2% of fractions with the adaptive-plan, the scheduled-plan in the remaining. The dispersion of the distributions of EUD_CTV-values from the 46 dose fractions differed significantly between the scheduled and adaptive plans (Ansari-Bradley-Test, p = 0.0158). Thus, the 2.5th percentile of the EUD_CTV-values by the adaptive plans amounted 97.1% (95% CI 96.6–99.5%) and by the scheduled plans 78.1% (95% CI 61.8–88.7%). While the EUD_CTV for the accumulated dose distributions stayed above 95% at PTV-margins of ≥ 3 mm for all 8 analyzed treatment phases the scheduled plans did for margins ≥ 5 mm. The intrafractional anatomic shifts of all 8 measured anatomic landmarks were smaller than the interfractional with overall median values of 8.5 mm and 5.5 mm (p < 0.0001 for five and p < 0.05 for all parameters, pairwise comparisons, signed-rank-test). The EUD_OAR-values for the larynx and the parotid gland were significantly lower for the adaptive compared with the scheduled plans (Wilcoxon-test, p < 0.001). Conclusions: The mobile tongue and tongue base showed considerable interfractional variations. While PTV-margins of 5 mm were sufficient for IGRT, ART showed the potential of decreasing PTV-margins and spare dose to the organs-at-risk.