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Background: To analyze the organization of multidisciplinary care pathways such as colorectal cancer care, an instrument was developed based on a recently published framework that was earlier used in analyzing (monodisciplinary) specialist cataract care from a lean perspective. Methods: The instrument was constructed using semi-structured interviews and direct observation of the colorectal care process based on a Rapid Plant Assessment. Six lean aspects that were earlier established that highly impact process design, were investigated: operational focus, autonomous work cell, physical lay-out of resources, multi-skilled team, pull planning and non-value adding activities. To test reliability, clarity and face validity of the instrument, a pilot study was performed in eight Dutch hospitals. Results: In the pilot it proved feasible to apply the instrument and generate the intended information. The instrument consisted of 83 quantitative and 24 qualitative items. Examples of results show differences in operational focus, number of patient visits needed for diagnosis, numbers of staff involved with treatment, the implementation of protocols and utilization of one-stop-shops. Identification of waste and non-value adding activities may need further attention. Based on feedback from involved clinicians the face validity was acceptable and the results provided useful feedback- and benchmark data. The instrument proved to be reliable and valid for broader implementation in Dutch health care. The limited number of cases made statistical analysis not possible and further validation studies may shed better light on variation. Conclusions: This paper demonstrates the use of an instrument to analyze organizational characteristics in colorectal cancer care from a lean perspective. Wider use might help to identify best organizational practices for colorectal surgery. In larger series the instrument might be used for in-depth research into the relation between organization and patient outcomes. Although we found no reason to adapt the underlying framework, recommendations were made for further development to enable use in different tumor- and treatment modalities and in larger (international) samples that allow for more advanced statistical analysis. Waste from defective care or from wasted human potential will need further elaboration of the instrument. [ABSTRACT FROM AUTHOR]

Background and Purpose: Concurrent chemo-radiotherapy (CCRT) followed by adjuvant durvalumab is standard-of-care for fit patients with unresectable stage III NSCLC. Intensity modulated proton therapy (IMPT) results in different doses to organs than intensity modulated photon therapy (IMRT). We investigated whether IMPT compared to IMRT reduce hematological toxicity and whether it affects durvalumab treatment., Materials and Methods: Prospectively collected series of consecutive patients with stage III NSCLC receiving CCRT between 06.16 and 12.22 (staged with FDG-PET-CT and brain imaging) were retrospectively analyzed. The primary endpoint was the incidence of lymphopenia grade ≥ 3 in IMPT vs IMRT treated patients., Results: 271 patients were enrolled (IMPT: n = 71, IMRT: n = 200) in four centers. All patients received platinum-based chemotherapy. Median age: 66 years, 58 % were male, 36 % had squamous NSCLC. The incidence of lymphopenia grade ≥ 3 during CCRT was 67 % and 47 % in the IMRT and IMPT group, respectively (OR 2.2, 95 % CI: 1.0-4.9, P = 0.03). The incidence of anemia grade ≥ 3 during CCRT was 26 % and 9 % in the IMRT and IMPT group respectively (OR = 4.9, 95 % CI: 1.9-12.6, P = 0.001). IMPT was associated with a lower rate of Performance Status (PS) ≥ 2 at day 21 and 42 after CCRT (13 % vs. 26 %, P = 0.04, and 24 % vs. 39 %, P = 0.02). Patients treated with IMPT had a higher probability of receiving adjuvant durvalumab (74 % vs. 52 %, OR 0.35, 95 % CI: 0.16-0.79, P = 0.01)., Conclusion: IMPT was associated with a lower incidence of severe lymphopenia and anemia, better PS after CCRT and a higher probability of receiving adjuvant durvalumab., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

In the treatment of Non-Hodgkin lymphoma (NHL), multiple therapeutic options are available. Improving outcome predictions are essential to optimize treatment. The metabolic active tumor volume (MATV) has shown to be a prognostic factor in NHL. It is usually retrieved using semi-automated thresholding methods based on standardized uptake values (SUV), calculated from 18 F-Fluorodeoxyglucose Positron Emission Tomography ( 18 F-FDG PET) images. However, there is currently no consensus method for NHL. The aim of this study was to review literature on different segmentation methods used, and to evaluate selected methods by using an in house created software tool. A software tool, MU ltiple S UV T hreshold (MUST)-segmenter was developed where tumor locations are identified by placing seed-points on the PET images, followed by subsequent region growing. Based on a literature review, 9 SUV thresholding methods were selected and MATVs were extracted. The MUST-segmenter was utilized in a cohort of 68 patients with NHL. Differences in MATVs were assessed with paired t-tests, and correlations and distributions figures. High variability and significant differences between the MATVs based on different segmentation methods ( p  < 0.05) were observed in the NHL patients. Median MATVs ranged from 35 to 211 cc. No consensus for determining MATV is available based on the literature. Using the MUST-segmenter with 9 selected SUV thresholding methods, we demonstrated a large and significant variation in MATVs. Identifying the most optimal segmentation method for patients with NHL is essential to further improve predictions of toxicity, response, and treatment outcomes, which can be facilitated by the MUST-segmenter., Competing Interests: The Department of Radiation Oncology has research collaborations with Elekta, IBA, RaySearch, Siemens, Mirada, Bergoz Instrumentation and Medical Data Works, Genentech. Dr. van Meerten reported research grants from Genentech, Celgene/BMS; personal fees from Kite/Gilead and Janssen (advisory boards); and honoraria from Kite/Gilead and Celgene/BMS (speaker fees) outside the submitted work., (© 2023 The Authors.)

Purpose: In the Netherlands, oesophageal cancer (EC) patients are selected for intensity modulated proton therapy (IMPT) using the expected normal tissue complication probability reduction (ΔNTCP) when treating with IMPT compared to volumetric modulated arc therapy (VMAT). In this study, we evaluate the robustness of the first EC patients treated with IMPT in our clinic in terms of target and organs-at-risk (OAR) dose with corresponding NTCP, as compared to VMAT., Materials and Methods: For 20 consecutive EC patients, clinical IMPT and VMAT plans were created on the average planning 4DCT. Both plans were robustly evaluated on weekly repeated 4DCTs and if target coverage degraded, replanning was performed. Target coverage was evaluated for complete treatment trajectories with and without replanning. The planned and accumulated mean lung dose (MLD) and mean heart dose (MHD) were additionally evaluated and translated into NTCP., Results: Replanning in the clinic was performed more often for IMPT (15x) than would have been needed for VMAT (8x) (p = 0.11). Both adaptive treatments would have resulted in adequate accumulated target dose coverage. Replanning in the first week of treatment had most clinical impact, as anatomical changes resulting in insufficient accumulated target coverage were already observed at this stage. No differences were found in MLD between the planned dose and the accumulated dose. Accumulated MHD differed from the planned dose (p < 0.001), but since these differences were similar for VMAT and IMPT (1.0 and 1.5 Gy, respectively), the ΔNTCP remained unchanged., Conclusion: Following an adaptive clinical workflow, adequate target dose coverage and stable OAR doses with corresponding NTCPs was assured for both IMPT and VMAT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The prognosis of patients with diffuse large B-cell lymphoma a primary refractory disease or relapsed within 12 months after autologous hematopoietic cell transplantation is poor with a median survival of only 6 months. With the new CD19-directed CAR T-cell therapy, 40% of the patients still achieve a long-term remission. However, this new treatment does bring new challenges such as bridging the time during the CAR T-cell product time, and recognition of treatment-related side effects such as cytokine release syndrome or neurotoxicity. Therefore, treatment by a dedicated, multidisciplinary team is necessary. Future research will focus on extending CAR T-cell therapy to other diseases and improve treatment in non-responsiveness or resistance to CAR-T cell 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., (Copyright © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Despite technical developments in treatment delivery, radiation-induced lung toxicity (RILT) remains a crucial problem in thoracic radiotherapy. Clinically based RILT scores have their limitations, and more objective measures such as pulmonary functions tests (PFTs) might help to improve treatment strategies., Purpose: To summarize the available evidence about the effect of dose to the lung in thoracic radiotherapy on forced expiratory volume in one second (FEV1) and diffusion capacity (DLCO) in patients with lung and esophageal cancer treated with curative intent., Material and Methods: A systematic review following the PRISMA guidelines was performed, using MEDLINE and including clinical studies using (chemo)radiotherapy (CRT) or stereotactic ablative radiotherapy (SABR) for lung or CRT for esophageal cancer that reported both lung dose-volume histogram (DVH) parameters and changes in PFT results. Search terms included lung and esophageal neoplasms, respiratory function tests, and radiotherapy., Results: Fifteen studies met the inclusion criteria. Seven out of 13 studies on lung cancer reported significant declines (defined as a p value < .05) in PFT results. Both esophageal studies reported significant DLCO declines. One SABR study found a correlation between low lung-dose parameters and FEV1 decline. Relations between decline of FEV1 (three studies) or decline of DLCO (five studies), respectively, and DVH parameters were found in eight studies analyzing CRT. Furthermore, a heterogeneous range of clinical risk factors for pulmonary function changes were reported in the selected studies., Conclusions: There is evidence that pulmonary function declines after RT in a dose-dependent manner, but solid data about lung DVH parameters predicting changes in PFT results are scarce. A major disadvantage was the wide variety of methods used, frequently lacking multivariable analyses. Studies using prospective high-quality data, analyzed with appropriate statistical methods, are needed. The Oncologist 2017;22:1257-1264 IMPLICATIONS FOR PRACTICE: Radiation-induced lung toxicity remains crucial in thoracic radiotherapy. To prevent this toxicity in the future and individualize patient treatment, objective measures of pulmonary toxicity are needed. Pulmonary function tests may provide such objective measures. This systematic review, included all available clinical studies using external beam radiotherapy for lung or esophageal cancer reporting pulmonary function combined with dose-volume histogram parameters. There is preliminary evidence that pulmonary function declines post radiotherapy in a dose-dependent manner. Data quality and analyses were generally limited. Analyses of high-quality data are therefore urgently needed to improve individualization of advanced radiation therapy., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2017.)

Background and Purpose: Radiotherapy plays a pivotal role in lung cancer treatment. Selection of patients for new (radio)therapeutic options aiming at improving outcomes requires reliable and validated prediction models. We present the implementation of a prospective platform for evaluation and development of lung radiotherapy (proPED-LUNG) as an instrument enabling multidimensional predictive modelling., Materials and Methods: ProPED-LUNG was designed to comprise relevant baseline and follow up data of patients receiving pulmonary radiotherapy with curative intent. Patient characteristics, diagnostic and staging information, treatment parameters including full dose-volume-histograms, tumour control, survival, and toxicity are scored. Besides physician-rated data, a range of patient-rated data regarding symptoms and health-related quality-of-life are collected., Results: After 18 months of accrual, 315 patients have been included (accrual rate, 18 per month). Of the first hundred patients included, 70 received conformal (chemo)radiotherapy and 30 underwent stereotactic radiotherapy. Compliance at 3 and 6 months follow-up was 96-100% for patient-rated, and 81-94% for physician-rated assessments. For data collection, 0.4 FTE were allocated in a 183 FTE department (0.2%)., Conclusions: ProPED-LUNG is feasible with high compliance rates and yields a large amount of high quality prospective disease-related, treatment-related, patient- and physician-rated data which can be used to evaluate new developments in pulmonary radiotherapy., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)