Evaluation of interplay and organ motion effects by means of 4D dose reconstruction and accumulation

PURPOSE: Pencil beam scanned proton therapy (PBS-PT) treatment quality might be compromised by interplay and motion effects. Via fraction-wise reconstruction of 4D dose distributions and dose accumulation, we assess the clinical relevance of motion related target dose degradation in thoracic cancer patients. METHODS AND MATERIALS: For the ten thoracic patients (Hodgkin lymphoma and non-small cell lung cancer) treated at our proton therapy facility, daily breathing pattern records, treatment delivery log-files and weekly repeated 4DCTs were collected. Patients exhibited point-max target motion of up to 20 mm. They received robustly optimized treatment plans, delivered with five-times rescanning in fractionated regimen. Treatment delivery records were used to reconstruct 4D dose distributions and the accumulated treatment course dose per patient. Fraction-wise target dose degradations were analyzed and the accumulated treatment course dose, representing an estimation of the delivered dose, was compared with the prescribed dose. RESULTS: No clinically relevant loss of target dose homogeneity was found in the fraction-wise reconstructed 4D dose distributions. Overall, in 97% of all reconstructed fraction doses, D98 remained within 5% from the prescription dose. The V95 of accumulated treatment course doses was higher than 99.7% for all ten patients. CONCLUSIONS: 4D dose reconstruction and accumulation enables the clinical estimation of actual exhibited interplay and motion effects. In the patients considered here, the loss of homogeneity caused by interplay and organ motion did not show systematic pattern and smeared out throughout the course of fractionated PBS-PT treatment. Dose degradation due to anatomical changes showed to be more severe and triggered treatment adaptations for five patients

Extranodal Natural Killer/T-cell Lymphoma, Nasal Type:Diagnosis and Treatment

The aggressive lymphoma, extranodal natural killer/T-cell lymphoma-nasal type, is strongly associated with Epstein-Barr virus (EBV) and is most common in Asia and in South and Central America. By contrast, incidence is low in the United States and Europe, where extranodal natural killer/T-cell lymphoma represents only 0.2%-0.4% of all newly diagnosed non-Hodgkin lymphomas. At diagnosis, it is important to test for EBV DNA in plasma by polymerase chain reaction and to carry out positron emission tomography/computer tomography and magnetic resonance imaging of the nasopharynx. In stage I/II disease, radiotherapy is the most important treatment modality, but in high-risk stage I/II disease (stage II, age > 60 y, elevated lactate dehydrogenase, Eastern Cooperative Oncology Group performance score ≥2, primary tumor invasion), it should be combined with chemotherapy. The most optimal responses are reached with nonmultidrug resistance-based therapy (eg, asparaginase- or platinum-based therapy). Therapeutic approaches consist of either platinum-based concurrent chemoradiotherapy or sequential chemoradiotherapy. The minimum dose of radiotherapy should be 50-56 Gy. Treatment of stage III/IV disease consists of 3 cycles of chemotherapy followed by autologous hematopoietic cell transplantation. Allogeneic hematopoietic cell transplantation should only be considered in case of relapsed disease or after difficulty reaching complete remission. During treatment and follow-up, plasma EBV levels should be monitored as a marker of tumor load

Updating Photon-Based Normal Tissue Complication Probability Models for Pneumonitis in Patients With Lung Cancer Treated With Proton Beam Therapy

Purpose: No validated models for predicting the risk of radiation pneumonitis (RP) with proton beam therapy (PBT) currently exist. Our goal was to externally validate and recalibrate multiple established photon-based normal tissue complication probability models for RP in a cohort with locally advanced nonsmall cell lung cancer treated with contemporary doses of chemoradiation using PBT. Methods and Materials: The external validation cohort consisted of 99 consecutive patients with locally advanced nonsmall cell lung cancer treated with chemoradiation using PBT. RP was retrospectively scored at 3 and 6 months posttreatment. We evaluated the performance of the photon Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) pneumonitis model, the QUANTEC model adjusted for clinical risk factors, and the newer Netherlands updated QUANTEC model. A closed testing procedure was performed to test the need for model updating, either by recalibration-in-the-large (re-estimation of intercept), recalibration (re-estimation of intercept/slope), or model revision (re-estimation of all coefficients). Results: There were 21 events (21%) of ≥grade 2 RP. The closed testing procedure on the PBT data set did not detect major deviations between the models and the data and recommended adjustment of the intercept only for the photon-based Netherlands updated QUANTEC model (intercept update: –1.2). However, an update of the slope and revision of the model coefficients were not recommended by the closed testing procedure, as the deviations were not significant within the power of the data. Conclusions: The similarity between the dose-response relationship for PBT and photons for normal tissue complications has been an assumption until now. We demonstrate that the preexisting, widely used photon based models fit our PBT data well with minor modifications. These now-validated and updated normal tissue complication probability models can aid in individualizing selection of the most optimal treatment technique for a particular patient

External validation of NTCP-models for radiation pneumonitis in lung cancer patients treated with chemoradiotherapy

PURPOSE: Normal tissue complication probability (NTCP) models can be used to estimate the risk of radiation pneumonitis (RP). The aim of this study was to externally validate the most frequently used prediction models for RP, i.e., the QUANTEC and APPELT models, in a large cohort of lung cancer patients treated with IMRT or VMAT. [1-2] METHODS AND MATERIALS: This prospective cohort study, included lung cancer patients treated between 2013 and 2018. A closed testing procedure was performed to test the need for model updating. To improve model performance, modification or removal of variables was considered. Performance measures included tests for goodness of fit, discrimination, and calibration.RESULTS: In this cohort of 612 patients, the incidence of RP ≥ grade 2 was 14.5%. For the QUANTEC-model, recalibration was recommended which resulted in a revised intercept and adjusted regression coefficient (from 0.126 to 0.224) of the mean lung dose (MLD),. The APPELT-model needed revision including model updating with modification and elimination of variables. After revision, the New RP-model included the following predictors (and regression coefficients): MLD (B = 0.250), age (B = 0.049, and smoking status (B = 0.902). The discrimination of the updated APPELT-model was higher compared to the recalibrated QUANTEC-model (AUC: 0.79 vs. 0.73).CONCLUSIONS: This study demonstrated that both the QUANTEC- and APPELT-model needed revision. Next to changes of the intercept and regression coefficients, the APPELT model improved further by model updating and performed better than the recalibrated QUANTEC model. This New RP-model is widely applicable containing non-tumour site specific variables, which can easily be collected.</p

Reducing and controlling metabolic active tumor volume prior to CAR T-cell infusion can improve survival outcomes in patients with large B-cell lymphoma

Bridging therapy before CD19-directed chimeric antigen receptor (CAR) T-cell infusion is frequently applied in patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). This study aimed to assess the influence of quantified MATV and MATV-dynamics, between pre-apheresis (baseline) and pre-lymphodepleting chemotherapy (pre-LD) MATV, on CAR T-cell outcomes and toxicities in patients with r/r LBCL. MATVs were calculated semi-automatically at baseline (n = 74) and pre-LD (n = 68) in patients with r/r LBCL who received axicabtagene ciloleucel. At baseline, patients with a low MATV (&lt; 190 cc) had a better time to progression (TTP) and overall survival (OS) compared to high MATV patients (p &lt; 0.001). High MATV patients who remained stable or reduced upon bridging therapy showed a significant improvement in TTP (p = 0.041) and OS (p = 0.015), compared to patients with a high pre-LD MATV (&gt; 480 cc). Furthermore, high MATV baseline was associated with severe cytokine release syndrome (CRS, p = 0.001). In conclusion, patients with low baseline MATV had the best TTP/OS and effective reduction or controlling MATV during bridging improved survival outcomes in patients with a high baseline MATV, providing rationale for the use of more aggressive bridging regimens

Reducing and controlling metabolic active tumor volume prior to CAR T-cell infusion can improve survival outcomes in patients with large B-cell lymphoma

Abstract Bridging therapy before CD19-directed chimeric antigen receptor (CAR) T-cell infusion is frequently applied in patients with relapsed or refractory Large B-cell lymphoma (r/r LBCL). This study aimed to assess the influence of quantified MATV and MATV-dynamics, between pre-apheresis (baseline) and pre-lymphodepleting chemotherapy (pre-LD) MATV, on CAR T-cell outcomes and toxicities in patients with r/r LBCL. MATVs were calculated semi-automatically at baseline (n = 74) and pre-LD (n = 68) in patients with r/r LBCL who received axicabtagene ciloleucel. At baseline, patients with a low MATV ( 480 cc). Furthermore, high MATV baseline was associated with severe cytokine release syndrome (CRS, p = 0.001). In conclusion, patients with low baseline MATV had the best TTP/OS and effective reduction or controlling MATV during bridging improved survival outcomes in patients with a high baseline MATV, providing rationale for the use of more aggressive bridging regimens

Population-Based External Validation of the EASIX Scores to Predict CAR T-Cell-Related Toxicities

Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) can hamper the clinical benefit of CAR T-cell therapy in patients with relapsed/refractory large B-cell lymphoma (r/r LBCL). To assess the risk of CRS and ICANS, the endothelial activation and stress index (EASIX), the modified EASIX (m-EASIX), simplified EASIX (s-EASIX), and EASIX with CRP/ferritin (EASIX-F(C)) were proposed. This study validates these scores in a consecutive population-based cohort. Patients with r/r LBCL treated with axicabtagene ciloleucel were included ( = 154). EASIX scores were calculated at baseline, before lymphodepletion (pre-LD) and at CAR T-cell infusion. The EASIX and the s-EASIX at pre-LD were significantly associated with ICANS grade = 2 (both = 0.04), and the EASIX approached statistical significance at infusion ( = 0.05). However, the predictive performance was moderate, with area under the curves of 0.61-0.62. Validation of the EASIX-FC revealed that patients in the intermediate risk group had an increased risk of ICANS grade = 2 compared to low-risk patients. No significant associations between EASIX scores and CRS/ICANS grade = 3 were found. The (m-/s-) EASIX can be used to assess the risk of ICANS grade = 2 in patients treated with CAR T-cell therapy. However, due to the moderate performance of the scores, further optimization needs to be performed before broad implementation as a clinical tool, directing early intervention and guiding outpatient CAR T-cell treatment