Clinician perspectives on clinical decision support systems in lung cancer: Implications for shared decision-making.

BACKGROUND: Lung cancer treatment decisions are typically made among clinical experts in a multidisciplinary tumour board (MTB) based on clinical data and guidelines. The rise of artificial intelligence and cultural shifts towards patient autonomy are changing the nature of clinical decision-making towards personalized treatments. This can be supported by clinical decision support systems (CDSSs) that generate personalized treatment information as a basis for shared decision-making (SDM). Little is known about lung cancer patients' treatment decisions and the potential for SDM supported by CDSSs. The aim of this study is to understand to what extent SDM is done in current practice and what clinicians need to improve it. OBJECTIVE: To explore (1) the extent to which patient preferences are taken into consideration in non-small-cell lung cancer (NSCLC) treatment decisions; (2) clinician perspectives on using CDSSs to support SDM. DESIGN: Mixed methods study consisting of a retrospective cohort study on patient deviation from MTB advice and reasons for deviation, qualitative interviews with lung cancer specialists and observations of MTB discussions and patient consultations. SETTING AND PARTICIPANTS: NSCLC patients (N = 257) treated at a single radiotherapy clinic and nine lung cancer specialists from six Dutch clinics. RESULTS: We found a 10.9% (n = 28) deviation rate from MTB advice; 50% (n = 14) were due to patient preference, of which 85.7% (n = 12) chose a less intensive treatment than MTB advice. Current MTB recommendations are based on clinician experience, guidelines and patients' performance status. Most specialists (n = 7) were receptive towards CDSSs but cited barriers, such as lack of trust, lack of validation studies and time. CDSSs were considered valuable during MTB discussions rather than in consultations. CONCLUSION: Lung cancer decisions are heavily influenced by clinical guidelines and experience, yet many patients prefer less intensive treatments. CDSSs can support SDM by presenting the harms and benefits of different treatment options rather than giving single treatment advice. External validation of CDSSs should be prioritized. PATIENT OR PUBLIC CONTRIBUTION: This study did not involve patients or the public explicitly; however, the study design was informed by prior interviews with volunteers of a cancer patient advocacy group. The study objectives and data collection were supported by Dutch health care insurer CZ for a project titled 'My Best Treatment' that improves patient-centeredness and the lung cancer patient pathway in the Netherlands.

Feature selection methodology for longitudinal cone-beam CT radiomics.

BACKGROUND: Cone-beam CT (CBCT) scans are typically acquired daily for positioning verification of non-small cell lung cancer (NSCLC) patients. Quantitative information, derived using radiomics, can potentially contribute to (early) treatment adaptation. The aims of this study were to (1) describe and investigate a methodology for feature selection of a longitudinal radiomics approach (2) investigate which time-point during treatment is potentially useful for early treatment response assessment. MATERIAL AND METHODS: For 90 NSCLC patients CBCT scans of the first two fractions of treatment (considered as 'test-retest' scans) were analyzed, as well as weekly CBCT images. One hundred and sixteen radiomic features were extracted from the GTV of all scans and subsequently absolute and relative differences were calculated between weekly CBCT images and the CBCT of the first fraction. Test-retest scans were used to determine the smallest detectable change (C = 1.96 * SD) allowing for feature selection by choosing a minimum number of patients for which a feature should change more than 'C' to be considered as relevant. Analysis of which features change at which moment during treatment was used to investigate which time-point is potentially relevant to extract longitudinal radiomics information for early treatment response assessment. RESULTS: A total of six absolute delta features changed for at least ten patients at week 2 of treatment and increased to 61 at week 3, 79 at week 4 and 85 at week 5. There was 93% overlap between features selected at week 3 and the other weeks. CONCLUSIONS: This study describes a feature selection methodology for longitudinal radiomics that is able to select reproducible delta radiomics features that are informative due to their change during treatment, which can potentially be used for treatment decisions concerning adaptive radiotherapy. Nonetheless, the prognostic value of the selected delta radiomic features should be investigated in future studies.

Predicting tumor hypoxia in non-small cell lung cancer by combining CT, FDG PET and dynamic contrast-enhanced CT.

BACKGROUND: Most solid tumors contain inadequately oxygenated (i.e., hypoxic) regions, which tend to be more aggressive and treatment resistant. Hypoxia PET allows visualization of hypoxia and may enable treatment adaptation. However, hypoxia PET imaging is expensive, time-consuming and not widely available. We aimed to predict hypoxia levels in non-small cell lung cancer (NSCLC) using more easily available imaging modalities: FDG-PET/CT and dynamic contrast-enhanced CT (DCE-CT). MATERIAL AND METHODS: For 34 NSCLC patients, included in two clinical trials, hypoxia HX4-PET/CT, planning FDG-PET/CT and DCE-CT scans were acquired before radiotherapy. Scans were non-rigidly registered to the planning CT. Tumor blood flow (BF) and blood volume (BV) were calculated by kinetic analysis of DCE-CT images. Within the gross tumor volume, independent clusters, i.e., supervoxels, were created based on FDG-PET/CT. For each supervoxel, tumor-to-background ratios (TBR) were calculated (median SUV/aorta SUVmean) for HX4-PET/CT and supervoxel features (median, SD, entropy) for the other modalities. Two random forest models (cross-validated: 10 folds, five repeats) were trained to predict the hypoxia TBR; one based on CT, FDG, BF and BV, and one with only CT and FDG features. Patients were split in a training (trial NCT01024829) and independent test set (trial NCT01210378). For each patient, predicted, and observed hypoxic volumes (HV) (TBR > 1.2) were compared. RESULTS: Fifteen patients (3291 supervoxels) were used for training and 19 patients (1502 supervoxels) for testing. The model with all features (RMSE training: 0.19 ± 0.01, test: 0.27) outperformed the model with only CT and FDG-PET features (RMSE training: 0.20 ± 0.01, test: 0.29). All tumors of the test set were correctly classified as normoxic or hypoxic (HV > 1 cm3) by the best performing model. CONCLUSIONS: We created a data-driven methodology to predict hypoxia levels and hypoxia spatial patterns using CT, FDG-PET and DCE-CT features in NSCLC. The model correctly classifies all tumors, and could therefore, aid tumor hypoxia classification and patient stratification.

Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion.

PURPOSE: Multiple imaging techniques are nowadays available for clinical in-vivo visualization of tumour biology. FDG PET/CT identifies increased tumour metabolism, hypoxia PET visualizes tumour oxygenation and dynamic contrast-enhanced (DCE) CT characterizes vasculature and morphology. We explored the relationships among these biological features in patients with non-small-cell lung cancer (NSCLC) at both the patient level and the tumour subvolume level. METHODS: A group of 14 NSCLC patients from two ongoing clinical trials (NCT01024829 and NCT01210378) were scanned using FDG PET/CT, HX4 PET/CT and DCE CT prior to chemoradiotherapy. Standardized uptake values (SUV) in the primary tumour were calculated for the FDG and hypoxia HX4 PET/CT scans. For hypoxia imaging, the hypoxic volume, fraction and tumour-to-blood ratio (TBR) were also defined. Blood flow and blood volume were obtained from DCE CT imaging. A tumour subvolume analysis was used to quantify the spatial overlap between subvolumes. RESULTS: At the patient level, negative correlations were observed between blood flow and the hypoxia parameters (TBR >1.2): hypoxic volume (-0.65, p = 0.014), hypoxic fraction (-0.60, p = 0.025) and TBR (-0.56, p = 0.042). At the tumour subvolume level, hypoxic and metabolically active subvolumes showed an overlap of 53 ± 36 %. Overlap between hypoxic sub-volumes and those with high blood flow and blood volume was smaller: 15 ± 17 % and 28 ± 28 %, respectively. Half of the patients showed a spatial mismatch (overlap <5 %) between increased blood flow and hypoxia. CONCLUSION: The biological imaging features defined in NSCLC tumours showed large interpatient and intratumour variability. There was overlap between hypoxic and metabolically active subvolumes in the majority of tumours, there was spatial mismatch between regions with high blood flow and those with increased hypoxia.

Modern clinical research: How rapid learning health care and cohort multiple randomised clinical trials complement traditional evidence based medicine.

BACKGROUND: Trials are vital in informing routine clinical care; however, current designs have major deficiencies. An overview of the various challenges that face modern clinical research and the methods that can be exploited to solve these challenges, in the context of personalised cancer treatment in the 21st century is provided. AIM: The purpose of this manuscript, without intending to be comprehensive, is to spark thought whilst presenting and discussing two important and complementary alternatives to traditional evidence-based medicine, specifically rapid learning health care and cohort multiple randomised controlled trial design. Rapid learning health care is an approach that proposes to extract and apply knowledge from routine clinical care data rather than exclusively depending on clinical trial evidence, (please watch the animation: http://youtu.be/ZDJFOxpwqEA). The cohort multiple randomised controlled trial design is a pragmatic method which has been proposed to help overcome the weaknesses of conventional randomised trials, taking advantage of the standardised follow-up approaches more and more used in routine patient care. This approach is particularly useful when the new intervention is a priori attractive for the patient (i.e. proton therapy, patient decision aids or expensive medications), when the outcomes are easily collected, and when there is no need of a placebo arm. DISCUSSION: Truly personalised cancer treatment is the goal in modern radiotherapy. However, personalised cancer treatment is also an immense challenge. The vast variety of both cancer patients and treatment options makes it extremely difficult to determine which decisions are optimal for the individual patient. Nevertheless, rapid learning health care and cohort multiple randomised controlled trial design are two approaches (among others) that can help meet this challenge.

Patient-reported outcomes after personalised dose-escalation for stage II-III non-small-cell lung cancer patients: Results from the randomised ARTFORCE PET-Boost trial.

BACKGROUND AND PURPOSE: The ultimate challenge in dose-escalation trials lies in finding the balance between benefit and toxicity. We examined patient-reported outcomes (PROs), including health-related quality of life (HRQoL) in patients with locally advanced non-small cell lung cancer (LA-NSCLC), treated with dose-escalated radiotherapy. MATERIALS AND METHODS: The international, randomised, phase 2 ARTFORCE PET-Boost study (NCT01024829) aimed to improve 1-year freedom from local failure rates in patients with stage II-III NSCLC, with a ≥ 4 cm primary tumour. Treatment consisted of an individualised, escalated fraction dose, either to the primary tumour as a whole or to its most FDG-avid subvolume (24 x 3.0-5.4 Gy). Patients received sequential or concurrent chemoradiotherapy, or radiotherapy only. Patients were asked to complete the EORTC QLQ-C30, QLQ-LC13, and the EuroQol-5D at eight timepoints. We assessed the effect of dose-escalation on C30 sum score through mixed-modelling and evaluated clinically meaningful changes for all outcomes. RESULTS: Between Apr-2010 and Sep-2017, 107 patients were randomised; 102 were included in the current analysis. Compliance rates: baseline 86.3%, 3-months 85.3%, 12-months 80.3%; lowest during radiation treatment 35.0%. A linear mixed-effect (LME) model revealed no significant change in overall HRQoL over time, and no significant difference between the two treatment groups. Physical functioning showed a gradual decline in both groups during treatment and at 18-months follow-up, while clinically meaningful worsening of dyspnoea was seen mainly at 3- and 6-months. CONCLUSION: In patients with LA-NSCLC treated with two dose-escalation strategies, the average patient-reported HRQoL remained stable in both groups, despite frequent patient-reported symptoms, including dyspnoea, dysphagia, and fatigue.

Prognostic value of metabolic metrics extracted from baseline positron emission tomography images in non-small cell lung cancer.

BACKGROUND: Maximum, mean and peak SUV of primary tumor at baseline FDG-PET scans, have often been found predictive for overall survival in non-small cell lung cancer (NSCLC) patients. In this study we further investigated the prognostic power of advanced metabolic metrics derived from intensity volume histograms (IVH) extracted from PET imaging. METHODS: A cohort of 220 NSCLC patients (mean age, 66.6 years; 149 men, 71 women), stages I-IIIB, treated with radiotherapy with curative intent were included (NCT00522639). Each patient underwent standardized pre-treatment CT-PET imaging. Primary GTV was delineated by an experienced radiation oncologist on CT-PET images. Common PET descriptors such as maximum, mean and peak SUV, and metabolic tumor volume (MTV) were quantified. Advanced descriptors of metabolic activity were quantified by IVH. These comprised five groups of features: absolute and relative volume above relative intensity threshold (AVRI and RVRI), absolute and relative volume above absolute intensity threshold (AVAI and RVAI), and absolute intensity above relative volume threshold (AIRV). MTV was derived from the IVH curves for volumes with SUV above 2.5, 3 and 4, and of 40% and 50% maximum SUV. Univariable analysis using Cox Proportional Hazard Regression was performed for overall survival assessment. RESULTS: Relative volume above higher SUV (80%) was an independent predictor of OS (p = 0.05). None of the possible surrogates for MTV based on volumes above SUV of 3, 40% and 50% of maximum SUV showed significant associations with OS [p (AVAI3) = 0.10, p (AVAI4) = 0.22, p (AVRI40%) = 0.15, p (AVRI50%) = 0.17]. Maximum and peak SUV (r = 0.99) revealed no prognostic value for OS [p (maximum SUV) = 0.20, p (peak SUV) = 0.22]. CONCLUSIONS: New methods using more advanced imaging features extracted from PET were analyzed. Best prognostic value for OS of NSCLC patients was found for relative portions of the tumor above higher uptakes (80% SUV).

18F-FDG-PET guided vs whole tumour radiotherapy dose escalation in patients with locally advanced non-small cell lung cancer (PET-Boost): Results from a randomised clinical trial.

BACKGROUND AND PURPOSE: We aimed to assess if radiation dose escalation to either the whole primary tumour, or to an 18F-FDG-PET defined subvolume within the primary tumour known to be at high risk of local relapse, could improve local control in patients with locally advanced non-small-cell lung cancer. MATERIALS AND METHODS: Patients with inoperable, stage II-III NSCLC were randomised (1:1) to receive dose-escalated radiotherapy to the whole primary tumour or a PET-defined subvolume, in 24 fractions. The primary endpoint was freedom from local failure (FFLF), assessed by central review of CT-imaging. A phase II 'pick-the-winner' design (alpha = 0.05; beta = 0.80) was applied to detect a 15 % increase in FFLF at 1-year. CLINICALTRIALS: gov:NCT01024829. RESULTS: 150 patients were enrolled. 54 patients were randomised to the whole tumour group and 53 to the PET-subvolume group. The trial was closed early due to slow accrual. Median dose/fraction to the boosted volume was 3.30 Gy in the whole tumour group, and 3.50 Gy in the PET-subvolume group. The 1-year FFLF rate was 97 % (95 %CI 91-100) in whole tumour group, and 91 % (95 %CI 82-100) in the PET-subvolume group. Acute grade ≥ 3 adverse events occurred in 23 (43 %) and 20 (38 %) patients, and late grade ≥ 3 in 12 (22 %) and 17 (32 %), respectively. Grade 5 events occurred in 19 (18 %) patients in total, of which before disease progression in 4 (7 %) in the whole tumour group, and 5 (9 %) in the PET-subvolume group. CONCLUSION: Both strategies met the primary objective to improve local control with 1-year rates. However, both strategies led to unexpected high rates of grade 5 toxicity. Dose differentiation, improved patient selection and better sparing of central structures are proposed to improve dose-escalation strategies.

The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R): Real-World Data on Stage III Non-Small Cell Lung Cancer Patients Treated With Curative Chemoradiation.

INTRODUCTION: Chemoradiotherapy (CRT) is the standard of care in inoperable non-small-cell lung cancer (NSCLC) patients, favoring concurrent (cCRT) over sequential CRT (seqCRT), with adjuvant immunotherapy in responders. Elderly and frail NSCLC patients have generally been excluded from trials in the past. In elderly patients however, the higher treatment related morbidity of cCRT, may outweigh the possible lower tumor control of seqCRT. For elderly patients with locally advanced NSCLC real-world data is essential to be able to balance treatment toxicity and treatment outcome. The aim of this study is to analyze acute toxicity and 3-month mortality of curative chemoradiation (CRT) in patients with stage III NSCLC and to analyze whether cCRT for elderly stage III NSCLC patients is safe. METHODS: The Dutch Lung Cancer Audit-Radiotherapy (DLCA-R) is a national lung cancer audit that started in 2013 for patients treated with curative intent radiotherapy. All Dutch patients treated for stage III NSCLC between 2015 and 2018 with seqCRT or cCRT for (primary or recurrent) stage III lung cancer are included in this population-based study. Information was collected on patient, tumor- and treatment characteristics and the incidence and severity of acute non-hematological toxicity (CTCAE-4 version 4.03) and mortality within 3 months after the end of radiotherapy. To evaluate the association between prognostic factors and outcome (acute toxicity and mortality within 3 months), an univariable and multivariable analysis was performed. The definition of cCRT was:radiotherapy started within 30 days after the start of chemotherapy. RESULTS: Out of all 20 Dutch departments of radiation oncology, 19 centers participated in the registry. A total of 2942 NSCLC stage III patients were treated with CRT. Of these 67.2% (n = 1977) were treated with cCRT (median age 66 years) and 32.8% (n = 965) were treated with seqCRT (median age 69 years). Good performance status (WHO 0-1) was scored in 88.6% for patients treated with cCRT and in 71.0% in the patients treated with seqCRT. Acute nonhematological 3-month toxicity (CTCAE grade ≥3 or radiation pneumonitis grade ≥2) was scored in 21.9% of the patients treated with cCRT and in 17.7% of the patients treated with seqCRT. The univariable analysis for acute toxicity showed significantly increased toxicity for cCRT (P = .008), WHO ≥2 (P = .006), and TNM IIIC (P = .031). The multivariable analysis for acute toxicity was significant for cCRT (P = .015), WHO ≥2 (P = .001) and TNM IIIC (P = .016). The univariable analysis for 3-month mortality showed significance for seqCRT (P = .025), WHO ≥2 (P < .001), higher cumulative radiotherapy dose (P < .001), higher gross tumor volume total (P = .020) and male patients (p < .001). None of these variables reached significance in the multivariable analysis for 3-month mortality. CONCLUSION: In this national lung cancer audit of inoperable NSCLC patients, 3-month toxicity was significantly higher in patients treated with cCRT (21.9% vs. 17.7% for seqCRT) higher TNM stage IIIC, and poor performance (WHO≥2) patients.The 3-months mortality was not significantly different for tested parameters. Age was not a risk factor for acute toxicity, nor 3 months mortality.

Shared decision-making for prophylactic cranial irradiation in extensive-stage small-cell lung cancer: an exploratory study.

BACKGROUND: Prophylactic cranial irradiation (PCI) offers extensive-stage small-cell lung cancer (ES-SCLC) patients a lower chance of brain metastasis and slightly longer survival but is associated with a short-term decline in quality of life due to side-effects. This tradeoff between survival and quality of life makes PCI suitable for shared decision-making (SDM), where patients and clinicians make treatment decisions together based on clinical evidence and patient preferences. Despite recent clinical practice guidelines recommending SDM for PCI in ES-SCLC, as well as the heavy disease burden, research into SDM for lung cancer has been scarce. This exploratory study presents patients' experiences of the SDM process and decisional conflict for PCI. METHODS: Radiation oncologists (n=7) trained in SDM applied it in making the PCI decision with ES-SCLC patients (n=25). We measured patients' preferred level of participation (Control Preferences Scale), the level of SDM according to both groups (SDM-Q-9 and SDM-Q-Doc), and patients' decisional conflict [decisional conflict scale (DCS)]. RESULTS: Seventy-nine percent of patients preferred a collaborative role in decision-making, and median SDM scores given by patients and clinicians were 80 (IQR: 75.6-91.1) and 85.2 (IQR: 78.7-88.9) respectively, indicating satisfaction with the process. However, patients experienced considerable decisional conflict. Over 50% lacked clarity about which choice was suitable for them and were unsure what to choose. Sixty-four percent felt they did not know enough about the harms and benefits of PCI, and 60% felt unable to judge the importance of the harms/benefits in their life. CONCLUSIONS: ES-SCLC patients prefer to be involved in their treatment choice for PCI but a substantial portion experiences decisional conflict. Better information provision and values clarification may support patients in making a choice that reflects their preferences.

Chloroquine combined with concurrent radiotherapy and temozolomide for newly diagnosed glioblastoma: a phase IB trial.

Treatment of glioblastoma xenografts with chloroquine results in macroautophagy/autophagy inhibition, resulting in a reduction of tumor hypoxia and sensitization to radiation. Preclinical data show that EGFRvIII-expressing glioblastoma may benefit most from chloroquine because of autophagy dependency. This study is the first to explore the safety, pharmacokinetics and maximum tolerated dose of chloroquine in combination with radiotherapy and concurrent daily temozolomide in patients with a newly diagnosed glioblastoma. This study is a single-center, open-label, dose-finding phase I trial. Patients received oral chloroquine daily starting one week before the course of chemoradiation (temozolomide 75 mg/m2/d) until the end of radiotherapy (59.4 Gy/33 fractions). Thirteen patients were included in the study (n = 6: 200 mg, n = 3: 300 mg, n = 4: 400 mg chloroquine). A total of 44 adverse events, possibly related to chloroquine, were registered including electrocardiogram QTc prolongation, irreversible blurred vision and nausea/vomiting resulting in cessation of temozolomide or delay of adjuvant cycles. The maximum tolerated dose was 200 mg chloroquine. Median overall survival was 16 months (range 2-32). Median survival was 11.5 months for EGFRvIII- patients and 20 months for EGFRvIII+ patients. A daily dose of 200 mg chloroquine was determined to be the maximum tolerated dose when combined with radiotherapy and concurrent temozolomide for newly diagnosed glioblastoma. Favorable toxicity and promising overall survival support further clinical studies.Abbreviations: AE: adverse events; CQ: chloroquine; DLT: dose-limiting toxicities; EGFR: epidermal growth factor receptor; GBM: glioblastoma; HCQ: hydroxychloroquine; IDH1/2: isocitrate dehydrogenase (NADP(+)) 1/2; MTD: maximum tolerated dose; CTC: National Cancer Institute Common Toxicity Criteria; MGMT: O-6-methylguanine-DNA methyltransferase; OS: overall survival; po qd: per os quaque die; SAE: serious adverse events; TMZ: temozolomide; WHO: World Health Organization.

Nitroglycerin as a radiosensitizer in non-small cell lung cancer: Results of a prospective imaging-based phase II trial.

BACKGROUND: Nitroglycerin is proposed as an agent to reduce tumour hypoxia by improving tumour perfusion. We investigated the potential of nitroglycerin as a radio-sensitizer in non-small cell lung cancer (NSCLC) and the potential of functional imaging for patient selection. MATERIAL AND METHODS: Trial NCT01210378 is a single arm phase II trial, designed to detect 15% improvement in 2-year overall survival (primary endpoint) in stage IB-IV NSCLC patients treated with radical (chemo-) radiotherapy and a Transiderm-Nitro 5 patch during radiotherapy. Patients underwent dynamic contrast-enhanced CTs (DCE-CT) and HX4 (hypoxia) PET/CTs before and after nitroglycerin. Secondary endpoints were progression-free survival, toxicity and the prognostic value of tumour perfusion/hypoxia at baseline and after nitroglycerin. RESULTS: The trial stopped after a futility analysis after 42 patients. At median follow-up of 41 months, two-year and median OS were 58% (95% CI: 44-78%) and 38 months (95% CI: 22-54 months), respectively. Nitroglycerin could not reduce tumour hypoxia. DCE-CT parameters did not correlate with OS, whereas hypoxic tumours had a worse OS (p = 0.029). Changes in high-uptake fraction of HX4 and tumour blood flow were negatively correlated (r = -0.650, p = 0.022). The heterogeneity in treatment modalities and patient characteristics combined with a small sample size made further subgroup analysis of survival results impossible. Toxicity related to nitroglyerin was limited to headache (17%) and hypotension (2.4%). CONCLUSION: Nitroglycerin did not improve OS of NSCLC patients treated with (chemo-)radiotherapy. A general ability of nitroglycerin to reduce hypoxia was not shown.

Electronic Health Record implementation in a large academic radiotherapy department: Temporarily disruptions but long-term benefits.

PURPOSE: To study the number of disruptions in patient processes in a radiotherapy centre after the replacement of an Electronic Health Record (EHR), integrating information tools for patient care and billing. METHODS: Our self-made Electronic Medical Record was replaced by a new EHR, including clinical path and workflow-management. A social-technological approach was used to reduce complexity. We measured disruptions in patient processes by the number and type of EHR related root causes and EHR-related incidents that reached patients, in our patient safety system 12 months before implementing the new EHR, 6 months after implementation (transition period) and 24 months after the transition period. We used Mann-Whitney U and X² tests to compare data before and after implementation. RESULTS: An increase of disruptions occurred only temporarily during 6 months. After this period, the number stabilized to the level before implementation while having more functionalities and benefits. Neither the number nor the severity of incidents reaching patients increased. CONCLUSIONS: Disruptions in patient processes are considered as a main barrier for implementing an EHR. Using a social/technical approach, the increase in disruptions did only temporarily occur and did not reach patients. We think it is important to share this insight with physicians because literature shows that their long-term opinion regarding the usefulness of the EHR is often based on the experience in the first months after implementation. Management of expectations is recommended. ADVANCES IN KNOWLEDGE: This study is the first of its kind measuring long-term effects of EHR on patient processes in radiotherapy.

Individualized accelerated isotoxic concurrent chemo-radiotherapy for stage III non-small cell lung cancer: 5-Year results of a prospective study.

BACKGROUND: Stage III non-small cell lung cancer (NSCLC) still has a poor prognosis. Prior studies with individualized, accelerated, isotoxic dose escalation (INDAR) with 3D-CRT showed promising results, especially in patients not treated with concurrent chemo-radiotherapy. We investigated if INDAR delivered with IMRT would improve the overall survival (OS) of stage III NSCLC patients treated with concurrent chemotherapy and radiotherapy. PATIENTS AND METHODS: Patients eligible for concurrent chemo-radiotherapy were entered in this prospective study. Radiotherapy was given to a dose of 45 Gy/30 fractions BID (1.5 Gy/fraction), followed by QD fractions of 2 Gy until a total dose determined by the normal tissue constraints. The primary endpoint was OS, secondary endpoints were loco-regional relapses and toxicity. RESULTS: From May 4, 2009 until April 26, 2012, 185 patients were included. The mean tumor dose was 66.0 ±â€¯12.8 Gy (36-73 Gy), delivered in a mean of 39.7 fractions in an overall treatment time of 38.2 days. The mean lung dose (MLD) was 17.3 Gy. The median OS was 19.8 months (95% CI 17.3-22.3) with a 5-year OS of 24.3%. Loco-regional failures as first site of recurrence occurred in 59/185 patients (31.8%). Isolated nodal failures (INF) were observed in 3/185 patients (1.6%). Dyspnea grade 3 was seen in 3.2% of patients and transient dysphagia grade 3 in 22%. CONCLUSIONS: INDAR with IMRT concurrently with chemotherapy did not lead to a sign of an improved OS in unselected stage III NSCLC patients.

Longitudinal radiomics of cone-beam CT images from non-small cell lung cancer patients: Evaluation of the added prognostic value for overall survival and locoregional recurrence.

BACKGROUND AND PURPOSE: The prognostic value of radiomics for non-small cell lung cancer (NSCLC) patients has been investigated for images acquired prior to treatment, but no prognostic model has been developed that includes the change of radiomic features during treatment. Therefore, the aim of this study was to investigate the potential added prognostic value of a longitudinal radiomics approach using cone-beam computed tomography (CBCT) for NSCLC patients. MATERIALS AND METHODS: This retrospective study includes a training dataset of 141 stage I-IV NSCLC patients and three external validation datasets of 94, 61 and 41 patients, all treated with curative intended (chemo)radiotherapy. The change of radiomic features extracted from CBCT images was summarized as the slope of a linear regression. The CBCT slope-features and CT-extracted features were used as input for a Cox proportional hazards model. Moreover, prognostic performance of clinical parameters was investigated for overall survival and locoregional recurrence. Model performances were assessed using the Kaplan-Meier curves and c-index. RESULTS: The radiomics model contained only CT-derived features and reached a c-index of 0.63 for overall survival and could be validated on the first validation dataset. No model for locoregional recurrence could be developed that validated on the validation datasets. The clinical parameters model could not be validated for either overall survival or locoregional recurrence. CONCLUSION: In this study we could not confirm our hypothesis that longitudinal CBCT-extracted radiomic features contribute to improved prognostic information. Moreover, performance of baseline radiomic features or clinical parameters was poor, probably affected by heterogeneity within and between datasets.

The acute and late toxicity results of a randomized phase II dose-escalation trial in non-small cell lung cancer (PET-boost trial).

BACKGROUND AND PURPOSE: The PET-boost randomized phase II trial (NCT01024829) investigated dose-escalation to the entire primary tumour or redistributed to regions of high pre-treatment FDG-uptake in inoperable non-small cell lung cancer (NSCLC) patients. We present a toxicity analysis of the 107 patients randomized in the study. MATERIALS AND METHODS: Patients with stage II-III NSCLC were treated with an isotoxic integrated boost of ≥72 Gy in 24 fractions, with/without chemotherapy and strict dose limits. Toxicity was scored until death according to the CTCAEv3.0. RESULTS: 77 (72%) patients were treated with concurrent chemoradiotherapy. Acute and late ≥G3 occurred in 41% and 25%. For concurrent (C) and sequential or radiotherapy alone (S), the most common acute ≥G3 toxicities were: dysphagia in 14.3% (C) and 3.3% (S), dyspnoea in 2.6% (C) and 6.7% (S), pneumonitis in 0% (C) and 6.7% (S), cardiac toxicity in 6.5% (C) and 3.3% (S). Seventeen patients died of which in 13 patients a possible relation to treatment could not be excluded. In 10 of these 13 patients progressive disease was scored. Fatal pulmonary haemorrhages and oesophageal fistulae were observed in 9 patients. CONCLUSION: Personalized dose-escalation in inoperable NSCLC patients results in higher acute and late toxicity compared to conventional chemoradiotherapy. The toxicity, however, was within the boundaries of the pre-defined stopping rules.

Radiation-Induced Lung Density Changes on CT Scan for NSCLC: No Impact of Dose-Escalation Level or Volume.

PURPOSE: Dose-escalation for patients with non-small cell lung cancer (NSCLC) in the positron emission tomography (PET)-boost trial (NCT01024829) exposes portions of normal lung tissue to high radiation doses. The relationship between lung parenchyma dose and density changes on computed tomography (CT) was analyzed. MATERIALS AND METHODS: The CT scans of 59 patients with stage IB to III NSCLC, randomized between a boost to the whole primary tumor and an integrated boost to its 50% SUVmax (maximum standardized uptake value) volume. Patients were treated with concurrent or sequential chemoradiation or radiation only. Deformable registration mapped the 3-month follow-up CT to the planning CT. Hounsfield unit differences (ΔHU) were extracted to assess lung parenchyma density changes. Equivalent dose in 2 Gy fractions (EQD2)-ΔHU response was described sigmoidally, and regional response variation was studied by polar analysis. Prognostic factors of ΔHU were obtained through generalized linear modeling. RESULTS: Saturation of ΔHU was observed above 60 Gy. No interaction was found between boost dose distribution (D1cc and V70Gy) and ΔHU at lower doses. ΔHU was lowest peripherally from the tumor and peaked posteriorly at 3 cm from the tumor border (3.1 HU/Gy). Right lung location was an independent risk factor for ΔHU (P = .02). CONCLUSIONS: No apparent increase of lung density changes at 3-month follow-up was observed above 60 Gy EQD2 for patients with NSCLC treated with (concurrent or sequential chemo) radiation. The mild response observed peripherally in the lung parenchyma might be exploited in plan optimization routines minimizing lung damage.

Targeting Hypoxia to Improve Non-Small Cell Lung Cancer Outcome.

Oxygen deprivation (hypoxia) in non-small cell lung cancer (NSCLC) is an important factor in treatment resistance and poor survival. Hypoxia is an attractive therapeutic target, particularly in the context of radiotherapy, which is delivered to more than half of NSCLC patients. However, NSCLC hypoxia-targeted therapy trials have not yet translated into patient benefit. Recently, early termination of promising evofosfamide and tarloxotinib bromide studies due to futility highlighted the need for a paradigm shift in our approach to avoid disappointments in future trials. Radiotherapy dose painting strategies based on hypoxia imaging require careful refinement prior to clinical investigation. This review will summarize the role of hypoxia, highlight the potential of hypoxia as a therapeutic target, and outline past and ongoing hypoxia-targeted therapy trials in NSCLC. Evidence supporting radiotherapy dose painting based on hypoxia imaging will be critically appraised. Carefully selected hypoxia biomarkers suitable for integration within future NSCLC hypoxia-targeted therapy trials will be examined. Research gaps will be identified to guide future investigation. Although this review will focus on NSCLC hypoxia, more general discussions (eg, obstacles of hypoxia biomarker research and developing a framework for future hypoxia trials) are applicable to other tumor sites.

Progression-Free Survival and Overall Survival Beyond 5 Years of NSCLC Patients With Synchronous Oligometastases Treated in a Prospective Phase II Trial (NCT 01282450).

INTRODUCTION: Two randomized studies have shown an increased progression-free survival (PFS) by adding a radical local treatment to systemic therapy in responding patients with oligometastatic NSCLC, but long-term data are lacking. We updated the results of our previous phase II trial with a minimal follow-up exceeding 7 years. METHODS: This is a prospective single-arm phase II trial. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). No previous response to systemic treatment was needed. RESULTS: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44 to 81 years). Twenty-nine (74%) had N2 or N3 disease; 17 (44%) brain, 7 (18%) bone, and 4 (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval: 7.6-19.4 months); 1-, 2-, 3-, 5-, and 6- year OS was 56.4%, 23.3%,12.8%, 10.3%, 7.7%, and 5.1%, respectively. Median PFS was 12.1 months (95% confidence interval: 9.6-14.3 months); 1-, 2-, 3-, 5-, and 6- year OS was 51.3%, 13.6%, %,12.8%, 7.7%, 7.7%, and 2.5%, respectively. Only three patients (7.7%) had a local recurrence. CONCLUSIONS: In patients who were not selected according to response to systemic treatment, the PFS at 5 years was 8%. Entering patients in trials combining local therapy with novel systemic agents (e.g., immunotherapy) remains mandatory.