Visually guided inspiration breath-hold facilitated with nasal high flow therapy in locally advanced lung cancer.

BACKGROUND AND PURPOSE: Reducing breathing motion in radiotherapy (RT) is an attractive strategy to reduce margins and better spare normal tissues. The objective of this prospective study (NCT03729661) was to investigate the feasibility of irradiation of non-small cell lung cancer (NSCLC) with visually guided moderate deep inspiration breath-hold (IBH) using nasal high-flow therapy (NHFT). MATERIAL AND METHODS: Locally advanced NSCLC patients undergoing photon RT were given NHFT with heated humidified air (flow: 40 L/min with 80% oxygen) through a nasal cannula. IBH was monitored by optical surface tracking (OST) with visual feedback. At a training session, patients had to hold their breath as long as possible, without and with NHFT. For the daily cone beam CT (CBCT) and RT treatment in IBH, patients were instructed to keep their BH as long as it felt comfortable. OST was used to analyze stability and reproducibility of the BH, and CBCT to analyze daily tumor position. Subjective tolerance was measured with a questionnaire at 3 time points. RESULTS: Of 10 included patients, 9 were treated with RT. Seven (78%) completed the treatment with NHFT as planned. At the training session, the mean BH length without NHFT was 39 s (range 15-86 s), and with NHFT 78 s (range 29-223 s) (p = .005). NHFT prolonged the BH duration by a mean factor of 2.1 (range 1.1-3.9s). The mean overall stability and reproducibility were within 1 mm. Subjective tolerance was very good with the majority of patients having no or minor discomfort caused by the devices. The mean inter-fraction tumor position variability was 1.8 mm (-1.1-8.1 mm;SD 2.4 mm). CONCLUSION: NHFT for RT treatment of NSCLC in BH is feasible, well tolerated and significantly increases the breath-hold duration. Visually guided BH with OST is stable and reproducible. We therefore consider this an attractive patient-friendly approach to treat lung cancer patients with RT in BH.

Geriatric Assessment for Older Patients with Non-small Cell Lung Cancer: Daily Practice of Centers Participating in the NVALT25-ELDAPT Trial.

INTRODUCTION: Geriatric assessment (GA) for older patients with lung cancer could provide insight into vulnerability, cognitive impairment, and risk of toxicity. Discontinuation and complications of intensive treatment could potentially be prevented in vulnerable and frail patients. This study aimed to evaluate current clinical practice of GA for older patients with lung cancer in the Netherlands and identify potential hurdles for implementation. METHODS: Pulmonologists and radiation oncologists participating in the NVALT25-ELDAPT trial completed an online questionnaire regarding current practice of GA, added value of GA for treatment decision-making and logistic barriers for patients with non-small cell lung cancer. RESULTS: 15 out of 17 centers responded. Three performed GA as standard procedure, three on indication, eight considered a frailty screening step before GA, and one did not perform GA. Suspicion of cognitive problems was mentioned most often as indication for GA and of added value for treatment decision-making, followed by older age, curative-intent treatment, and stage I-III lung cancer. Administered instruments for screening and extensive GA were diverse. Main barriers to implement GA in clinical practice were logistic problems (timescales and availability of trained personnel). CONCLUSION: The use of GA in clinical practice for patients with lung cancer varied widely across centers regarding instruments and domains. Physicians are uniform in their opinion about indications for GA and the added value for treatment decision-making. Research should focus on manageable instruments and important domains to assess for this heterogeneous group of older patients with lung cancer to optimize treatment selection. Trial registration The NVALT25-ELDAPT trial is registered under trial number NCT02284308. Details are available at http://www.eldapt.org (predominantly in Dutch).

Evaluation of novel radiotherapy technologies: what evidence is needed to assess their clinical and cost effectiveness, and how should we get it?

Technical innovations in radiation oncology--eg, intensity-modulated radiotherapy, stereotactic radiotherapy, and particle therapy--can be developed rapidly and introduced into the clinic even when costs associated with their use are much higher than those for conventional radiotherapy. Although clinical benefit is expected on the basis of superior biological and physical characteristics, data for clinical effectiveness of new radiotherapy techniques are scarce. Evidence from randomised clinical trials would be ideal but such studies focus mostly on new drugs. High investment costs and modifications over time make evaluation of novel radiotherapy technologies in clinical trials more complex. Here, we propose an algorithm for evaluation of the clinical and cost effectiveness of novel radiotherapy technologies. We suggest situations when randomised trials might be feasible and the type of trial that should be undertaken when they are not. Furthermore, we discuss the usefulness of dose-distribution models for estimation of expected clinical benefit and for selection of the patients' population with the highest expected benefit. Economic modelling, including the approach of real options analysis, can inform whether implementation of a technology should begin (based on available evidence) or be delayed (until further data are available), and it can indicate the best trial design and required sample size.

Comparison of photon intensity modulated, hybrid and volumetric modulated arc radiation treatment techniques in locally advanced non-small cell lung cancer.

Background and purpose: There is no consensus on the best photon radiation technique for non-small cell lung cancer (NSCLC). This study quantified the differences between commonly used treatment techniques in NSCLC to find the optimal technique. Materials and methods: Treatment plans were retrospectively generated according to clinical guidelines for 26 stage III NSCLC patients using intensity modulated radiation therapy (IMRT), hybrid, and volumetric modulated arc therapy (VMATC, and VMATV5 optimized for lower lung and heart dose). Plans were evaluated for target coverage, organs at risk dose (including heart substructures) and normal tissue complication probabilities (NTCP). Results: The comparison showed significant and largest median differences (>1 Gy or >5%) in favor of IMRT for the mediastinal envelope and heart (maximum dose), in favor of the hybrid technique for the lungs (V5Gy of the total lungs and V5Gy of the contralateral lung) and in favor of VMATC for the heart (Dmean), most of the substructures of the heart, and the spinal cord (maximum dose). The VMATV5 technique had significantly lower heart dose compared to the hybrid technique and significantly lower lung dose compared to the VMATC, combining both advantages in one technique. The mean ΔNTCP did not exceed the 2 percent point (pp) for grade 5 (mortality), and 10 pp for grade ≥2 toxicities (radiation pneumonitis and acute esophageal toxicity), but ΔNTCP was mostly in favor of VMATC/V5 for individual patients. Conclusion: This planning study showed that VMATV5 was preferred as it achieved low lung and heart doses, as well as low NTCPs, simultaneously.

Clinical evaluation of synthetic computed tomography methods in adaptive proton therapy of lung cancer patients.

Background and purpose: Efficient workflows for adaptive proton therapy are of high importance. This study evaluated the possibility to replace repeat-CTs (reCTs) with synthetic CTs (sCTs), created based on cone-beam CTs (CBCTs), for flagging the need of plan adaptations in intensity-modulated proton therapy (IMPT) treatment of lung cancer patients. Materials and methods: Forty-two IMPT patients were retrospectively included. For each patient, one CBCT and a same-day reCT were included. Two commercial sCT methods were applied; one based on CBCT number correction (Cor-sCT), and one based on deformable image registration (DIR-sCT). The clinical reCT workflow (deformable contour propagation and robust dose re-computation) was performed on the reCT as well as the two sCTs. The deformed target contours on the reCT/sCTs were checked by radiation oncologists and edited if needed. A dose-volume-histogram triggered plan adaptation method was compared between the reCT and the sCTs; patients needing a plan adaptation on the reCT but not on the sCT were denoted false negatives. As secondary evaluation, dose-volume-histogram comparison and gamma analysis (2%/2mm) were performed between the reCT and sCTs. Results: There were five false negatives, two for Cor-sCT and three for DIR-sCT. However, three of these were only minor, and one was caused by tumour position differences between the reCT and CBCT and not by sCT quality issues. An average gamma pass rate of 93% was obtained for both sCT methods. Conclusion: Both sCT methods were judged to be of clinical quality and valuable for reducing the amount of reCT acquisitions.

A traffic light protocol workflow for image-guided adaptive radiotherapy in lung cancer patients.

BACKGROUND AND PURPOSE: Image-guided radiotherapy using cone beam-CT (CBCT) images is used to evaluate patient anatomy and positioning before radiotherapy. In this study we analyzed and optimized a traffic light protocol (TLP) used in lung cancer patients to identify patients requiring treatment adaptation. MATERIALS AND METHODS: First, CBCT review requests of 243 lung cancer patients were retrospectively analyzed and divided into 6 pre-defined categories. Frequencies and follow-up actions were scored. Based on these results, the TLP was optimized and evaluated in the same way on 230 patients treated in 2018. RESULTS: In the retrospective study, a total of 543 CBCT review requests were created during treatment in 193/243 patients due to changed anatomy of lung (24%), change of tumor volume (24%), review of match (18%), shift of the mediastinum (15%), shift of tumor (15%) and other (4%). The majority of requests (474, 87%) did not require further action. In 6% an adjustment of the match criteria sufficed; in 7% treatment plan adaptation was required. Plan adaptation was frequently seen in the categories changed anatomy of lung, change of tumor volume and shift of tumor outside the PTV. Shift of mediastinum outside PRV and shift of GTV outside CTV (but inside PTV) never required plan adaptation and were omitted to optimize the TLP, which reduced the CBCT review requests by 23%. CONCLUSIONS: The original TLP selected patients that required a treatment adaptation, but with a high false positive rate. The optimized TLP reduced the amount of CBCT review requests, while still correctly identifying patients requiring adaptation.

Prediction models for treatment-induced cardiac toxicity in patients with non-small-cell lung cancer: A systematic review and meta-analysis.

BACKGROUND: To maximize the likelihood of positive outcome in non-small-cell lung cancer (NSCLC) survivors, potential benefits of treatment modalities have to be weighed against the possibilities of damage to normal tissues, such as the heart. High-quality data-driven evidence regarding appropriate risk stratification strategies is still scarce. The aim of this review is to summarize and appraise available prediction models for treatment-induced cardiac events in patients with NSCLC. METHODS: A systematic search of MEDLINE was performed using a Boolean combination of appropriate truncation and indexing terms related to "NSCLC", "prediction models", "cardiac toxicity", and "treatment modalities". The following exclusion criteria were applied: sample-size of less than 100, no significant predictors in multivariate analysis, lack of model specifications, and case-mix studies. The generic inverse variance method was used to pool the summary effect estimate for each predictor. The quality of the papers was assessed using the Prediction model Risk Of Bias Assessment Tool. RESULTS: Of the 3,056 papers retrieved, 28 prediction models were identified, including seven for (chemo-)radiotherapy, one for immunotherapy, and 20 for surgical resection. Forty-one distinct predictors were entered in the prediction models. The pooled effect estimate of the mean heart dose (HR = 1.06, 95%CI:1.04-1.08) and history of cardiovascular diseases (HR = 3.1, 95%CI:1.8-5.36) were shown to significantly increase the risk of developing late cardiac toxicity after (chemo-)radiotherapy. Summary estimates of age (OR = 1.17, 95%CI:1.06-1.29), male gender (OR = 1.61, 95%CI:1.4-1.85), and advanced stage (OR = 1.34, 95%CI:1.06-1.69) were significantly associated with higher risk of acute cardiac events after surgery. Risk of bias varied across studies, but analysis was the most concerning domain where none of the studies were judged to be low risk. CONCLUSION: This review highlights the need for a robust prediction model which can inform patients and clinicians about expected treatment-induced heart damage. Identified clues suggest incorporation of detailed cardiac metrics (substructures' volumes and doses).

Treatment planning and 4D robust evaluation strategy for proton therapy of lung tumors with large motion amplitude.

PURPOSE: Intensity-modulated proton therapy (IMPT) for lung tumors with a large tumor movement is challenging due to loss of robustness in the target coverage. Often an upper cut-off at 5-mm tumor movement is used for proton patient selection. In this study, we propose (1) a robust and easily implementable treatment planning strategy for lung tumors with a movement larger than 5 mm, and (2) a four-dimensional computed tomography (4DCT) robust evaluation strategy for evaluating the dose distribution on the breathing phases. MATERIALS AND METHODS: We created a treatment planning strategy based on the internal target volume (ITV) concept (aim 1). The ITV was created as a union of the clinical target volumes (CTVs) on the eight 4DCT phases. The ITV expanded by 2 mm was the target during robust optimization on the average CT (avgCT). The clinical plan acceptability was judged based on a robust evaluation, computing the voxel-wise min and max (VWmin/max) doses over 28 error scenarios (range and setup errors) on the avgCT. The plans were created in RayStation (RaySearch Laboratories, Stockholm, Sweden) using a Monte Carlo dose engine, commissioned for our Mevion S250i Hyperscan system (Mevion Medical Systems, Littleton, MA, USA). We developed a new 4D robust evaluation approach (4DRobAvg; aim 2). The 28 scenario doses were computed on each individual 4DCT phase. For each scenario, the dose distributions on the individual phases were deformed to the reference phase and combined to a weighted sum, resulting in 28 weighted sum scenario dose distributions. From these 28 scenario doses, VWmin/max doses were computed. This new 4D robust evaluation was compared to two simpler 4D evaluation strategies: re-computing the nominal plan on each individual 4DCT phase (4DNom) and computing the robust VWmin/max doses on each individual phase (4DRobInd). The treatment planning and dose evaluation strategies were evaluated for 16 lung cancer patients with tumor movement of 4-26 mm. RESULTS: The ratio of the ITV and CTV volumes increased linearly with the tumor amplitude, with an average ratio of 1.4. Despite large ITV volumes, a clinically acceptable plan fulfilling all target and organ at risk (OAR) constraints was feasible for all patients. The 4DNom and 4DRobInd evaluation strategies were found to under- or overestimate the dosimetric effect of the tumor movement, respectively. 4DRobInd showed target underdosage for five patients, not observed in the robust evaluation on the avgCT or in 4DRobAvg. The accuracy of dose deformation used in 4DRobAvg was quantified and found acceptable, with differences for the dose-volume parameters below 1 Gy in most cases. CONCLUSION: The proposed ITV-based planning strategy on the avgCT was found to be a clinically feasible approach with adequate tumor coverage and no OAR overdosage even for large tumor movement. The new proposed 4D robust evaluation, 4DRobAvg, was shown to give an easily interpretable understanding of the effect of respiratory motion dose distribution, and to give an accurate estimate of the dose delivered in the different breathing phases.

PET imaging of hypoxia using [18F]HX4: a phase I trial.

BACKGROUND AND PURPOSE: Noninvasive PET imaging of tumour hypoxia could help in the selection of those patients who could benefit from chemotherapy or radiation with specific antihypoxic treatments such as bioreductive drugs or hypoxic radiosensitizers. In this phase I trial, we aimed to determine the toxicity of [(18)F]HX4, a member of the 2-nitroimidazole family, at different dose levels. The secondary aim was to analyse image quality related to the HX4 dose and the timing of imaging. METHODS: Patients with a histologically proven solid cancer without curative treatment options were eligible for this study. A study design with two dose steps was used in which a single dose of a maximum of 222 MBq (step 1) or 444 MBq (step 2) [(18)F]HX4 was injected. Toxicity was scored on day 0 and on days 3 and 7 after injection, according to the CTCAE 3.0 scoring system. PET/CT images of the largest tumour site were acquired 30, 60 and 120 min after injection. RESULTS: Six patients with stage IV carcinoma were included, four with non-small-cell lung carcinoma, one with thymus carcinoma, and one with colon carcinoma. No toxicity was observed in any of the patients at either dose level. The median tumour to muscle ratio 120 min after injection was 1.40 (range 0.63-1.98). CONCLUSION: The findings of this study showed that [(18)F]HX4 PET imaging for the detection of hypoxia is not associated with any toxicity. Imaging was successful; however, future trials are needed to determine the optimal image parameters.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: a planning study.

BACKGROUND AND PURPOSE: To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). MATERIAL AND METHODS: Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. RESULTS: FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. CONCLUSIONS: Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.

Comparison of SUVmax and SUVpeak based segmentation to determine primary lung tumour volume on FDG PET-CT correlated with pathology data.

PURPOSE: The aim of the study was to compare simple SUVmax and SUVpeak based segmentation methods for calculating the lung tumour volume, compared to a pathology ground truth. METHODS: Thirty patients diagnosed with early stage Non-Small Cell lung cancer (NSCLC) underwent surgical resection in the Netherlands between 2006 and 2008. FDG PET-CT scans for these patients were acquired within a median of 20 days before surgery. The tumour volume for each percentage SUVmax and SUVpeak threshold, with and without background correction, was calculated for each patient. The percentage threshold that provided the tumour volume that corresponded best with the pathology volume was considered to be the optimal threshold. The optimal thresholds were plotted as a function of tumour volume using a power law function and cross validated using the leave-one-out technique. RESULTS: The mean optimal percentage threshold was 50% ±â€¯10% and 62% ±â€¯15% for the SUVmax and SUVpeak without background correction respectively and 47% ±â€¯10% and 60 ±â€¯15% for the SUVmax and SUVpeak with background correction respectively. The optimal threshold curves could be fitted well with power law function. After cross validation the correlation between the effective tumour diameter in pathology and autosegmentation was 0.900 and 0.905 for the SUVmax and SUVpeak without background correction respectively and 0.913 and 0.908 for the SUVmax and SUVpeak with background correction respectively. CONCLUSION: No benefit was shown on clinical data for the SUVpeak based segmentation method over a SUVmax based one. Both methods can be used to determine the tumour volumes in resected NSCLC tumours.

Study Protocol of the NVALT25-ELDAPT Trial: Selecting the Optimal Treatment for Older Patients With Stage III Non-small-cell Lung Cancer.

BACKGROUND: Patients aged 75 years or older with stage III non-small-cell lung cancer (NSCLC) are underrepresented in clinical trials, leading to a lack of evidence for selection of the optimal treatment strategy. Information on benefits and harms of concurrent chemoradiotherapy among medically fit elderly patients is largely unknown, and reliable tools are needed to distinguish fit from frail patients for treatment selection. Also, information regarding quality of life during and after treatment is scarce. PATIENTS AND METHODS: This multicenter NVALT25-ELDAPT (Dutch Association of Chest Physicians Trial Number 25 - Elderly with locally advanced Lung cancer: Deciding through geriatric Assessment on the oPtimal Treatment strategy) trial (NCT02284308) consists of a phase III randomized trial in combination with an observational study for all patients who do not participate in the randomized trial. The first aim of this study is to develop a reliable and clinically applicable screening tool to distinguish medically fit from frail patients. All patients ≥ 75 years diagnosed with stage III NSCLC are invited to undergo extensive geriatric assessment (part I). The second aim is to compare treatment tolerance, survival, and quality of life between concurrent and sequential chemoradiotherapy in fit patients (randomized trial, part II). For all patients, overall survival adjusted for quality of life (quality-adjusted survival) is described for each category of fitness and treatment strategy during and after treatment. CONCLUSION: With the results of the NVALT25-ELDAPT trial, treatment selection can be optimized and the best possible outcomes for each individual older patient with stage III NSCLC can be achieved.

Patterns of treatment and survival among older patients with stage III non-small cell lung cancer.

INTRODUCTION: Patterns of treatment and survival are largely unknown for older patients with stage III non-small cell lung cancer (NSCLC) in daily clinical practice. METHODS: All patients ≥65 years with stage III NSCLC (2009-2013) were included from the population-based Netherlands Cancer Registry. Descriptive and multivariable treatment and survival analyses were stratified for patients aged 65-74 years and ≥75 years. RESULTS: Compared to older patients (n = 3163), those aged 65-74 years (n = 3876) underwent more often surgery (21% vs 12% for stage IIIA), chemoradiotherapy (47% vs 22% for both stage IIIA and IIIB), and chemotherapy (23% vs 12% for stage IIIB), and received less radiotherapy (8% vs 22% for both stage IIIA and IIIB). One-year survival was significantly higher among patients aged 65-74 compared to those aged ≥75 (61% vs 43%, for stage IIIA and 45% vs 30% for stage IIIB; P < .01). However, stratification of treatment showed similar survival rates between age groups. Among patients aged 65-74 years, the multivariably adjusted hazard ratio (HR) of death was twice as high for patients receiving radiotherapy (HR 1.9 (95%CI 1.6-2.2) for stage IIIA and HR 2.5 (95%CI 2.1-3.0) for stage IIIB) and chemotherapy (HR 2.2 (95%CI 1.9-2.5) and HR 2.2 (95%CI 1.8-2.7), respectively) compared to chemoradiotherapy, and were slightly lower for patients aged ≥75 years receiving radiotherapy (HR 1.6 (95%CI 1.4-1.9) and HR 1.8 (95%CI 1.5-2.1), respectively) and chemotherapy (HR 2.2 (95%CI 1.8-2.7) and HR 1.8 (95%CI 1.5-2.2), respectively). Comorbidity was not significantly associated with poorer survival (p = .07). CONCLUSION: Chemoradiotherapy was more often applied among patients aged 65-74 years compared to those aged ≥75. While survival was worse for patients aged ≥75 years, differences between age groups largely disappeared after stratification for treatment. Future research should focus on predictive patient characteristics to distinguish patients within the heterogeneous older population who can benefit from curative-intent treatment.

The Prevention of Brain Metastases in Non-Small Cell Lung Cancer by Prophylactic Cranial Irradiation.

BACKGROUND: Non-small cell lung cancer (NSCLC) patients frequently develop brain metastases (BM), even though the initial imaging with brain CT or MRI was negative. Stage III patients have the highest risk to develop BM, with an incidence of approximately 30%. BM can lead to neurocognitive disorders, loss of quality of life (QoL), and they are the most important factors influencing patient's overall survival (OS). Although a radical local treatment of BM may be possible with primary radiosurgery or after resection, the prognosis often remains poor. Preventing the development of BM through prophylactic cranial irradiation (PCI) may improve the outcome of these patients. METHODS: Data from published randomized trials comparing PCI with non-PCI were sought using electronic database (PubMed) searching, hand searching, and by contacting experts. Trials were included if they considered a randomized comparison of PCI and non-PCI, enrolled NSCLC patients, excluded patients with recurrent or metastatic disease, and reported results on BM occurrence. Each randomized controlled trial (RCT) was assessed for methodological quality using the Cochrane collaboration's tool for the assessment of risk of bias. Study estimates were pooled using a fixed effects sample-weighted meta-analysis approach to calculate an overall estimate and 95% confidence interval (CI). Results on PCI-related toxicity, QoL, and OS were only reported descriptively. RESULTS: Seven RCTs were included in the meta-analysis. In total, 1,462 patients were analyzed, including 717 patients who received PCI and 745 patients who did not. The risk of developing BM was significantly decreased through PCI (13% reduction, RR 0.33; 95% CI 0.22-0.45). PCI-related toxicity and QoL data were limited. Acute toxicity mostly included fatigue, skin-related toxicity, and nausea or vomiting. Late toxicities such as headache, dyspnea, lethargy, and low grade cognitive impairments were also reported in some of the included RCTs. Results on OS were inconclusive. CONCLUSION: The risk of developing BM was reduced in patients who received PCI compared to patients who did not. To implement PCI as the standard treatment for patients with NSCLC, the impact of PCI-related toxicity on QoL should be further investigated, as well as long-term OS. A future individual patient data meta-analysis could produce definitive answers to this clinical question.

Comparative evaluation of autocontouring in clinical practice: A practical method using the Turing test.

PURPOSE: Automated techniques for estimating the contours of organs and structures in medical images have become more widespread and a variety of measures are available for assessing their quality. Quantitative measures of geometric agreement, for example, overlap with a gold-standard delineation, are popular but may not predict the level of clinical acceptance for the contouring method. Therefore, surrogate measures that relate more directly to the clinical judgment of contours, and to the way they are used in routine workflows, need to be developed. The purpose of this study is to propose a method (inspired by the Turing Test) for providing contour quality measures that directly draw upon practitioners' assessments of manual and automatic contours. This approach assumes that an inability to distinguish automatically produced contours from those of clinical experts would indicate that the contours are of sufficient quality for clinical use. In turn, it is anticipated that such contours would receive less manual editing prior to being accepted for clinical use. In this study, an initial assessment of this approach is performed with radiation oncologists and therapists. METHODS: Eight clinical observers were presented with thoracic organ-at-risk contours through a web interface and were asked to determine if they were automatically generated or manually delineated. The accuracy of the visual determination was assessed, and the proportion of contours for which the source was misclassified recorded. Contours of six different organs in a clinical workflow were for 20 patient cases. The time required to edit autocontours to a clinically acceptable standard was also measured, as a gold standard of clinical utility. Established quantitative measures of autocontouring performance, such as Dice similarity coefficient with respect to the original clinical contour and the misclassification rate accessed with the proposed framework, were evaluated as surrogates of the editing time measured. RESULTS: The misclassification rates for each organ were: esophagus 30.0%, heart 22.9%, left lung 51.2%, right lung 58.5%, mediastinum envelope 43.9%, and spinal cord 46.8%. The time savings resulting from editing the autocontours compared to the standard clinical workflow were 12%, 25%, 43%, 77%, 46%, and 50%, respectively, for these organs. The median Dice similarity coefficients between the clinical contours and the autocontours were 0.46, 0.90, 0.98, 0.98, 0.94, and 0.86, respectively, for these organs. CONCLUSIONS: A better correspondence with time saving was observed for the misclassification rate than the quantitative contour measures explored. From this, we conclude that the inability to accurately judge the source of a contour indicates a reduced need for editing and therefore a greater time saving overall. Hence, task-based assessments of contouring performance may be considered as an additional way of evaluating the clinical utility of autosegmentation methods.

Predictors for poor cosmetic outcome in patients with early stage breast cancer treated with breast conserving therapy: Results of the Young boost trial.

PURPOSE: In the Young Boost trial (YBT), breast cancer patients ≤50 years of age, treated with breast conserving therapy (BCT) were randomized between a 26 Gy boost dose and a 16 Gy boost dose, with local recurrence as primary and cosmetic outcome (CO) as secondary endpoint. Data of the YBT was used to investigate which factors are related with worse cosmetic outcome after BCT. METHODS: From 2004 to 2011, 2421 cT1-2N0-2a breast cancer patients were randomized. CO was scored subjectively by the patient and physician, and objectively using BCCT.core: at baseline, one and four years after treatment. Associations between potential risk factors for worse cosmetic outcome, based on the objective BCCT.core, were investigated using a proportional odds model. RESULTS: At four years, CO was significantly better in the standard boost group for all three scoring methods (satisfied CO ±65% vs 55%). A photon boost, high boost dose, poor cosmesis before radiation therapy, large boost volume and adjuvant chemotherapy significantly deteriorated CO. CONCLUSION: Important risk factors for worse CO were the use of a photon boost instead of an electron boost, a high boost dose, cosmesis at baseline, adjuvant chemotherapy and boost volume. These results can be used to define strategies aimed at improving CO.

Trends in treatment and relative survival among Non-Small Cell Lung Cancer patients in the Netherlands (1990-2014): Disparities between younger and older patients.

BACKGROUND: This study aimed to describe trends over time regarding disparities in treatment and relative survival (RS) between younger and older patients with non-small cell lung cancer (NSCLC). METHODS: All patients diagnosed with pathologically verified NSCLC in 1990-2014 were included from the Netherlands Cancer Registry (n=187,315). Treatment and RS (adjusted for sex, histology and treatment) were analyzed according to age group (<70 years versus ≥70 years), stage and five-year period of diagnosis. RESULTS: Between 1990 and 2014, five-year RS increased from 17 to 22% among younger patients and from 12 to 16% among elderly. The application of surgery increased over time for elderly with stage I NSCLC, decreased for elderly with stage II, and was stable but higher for younger patients. Disparities in RS between age groups with stage I became smaller since 2000-2004, but did not change over time for stage II. For stage III and IV, both age groups showed strong increases over time in chemoradiotherapy and chemotherapy from 2000 onwards, although considerably less among elderly. One-, three- and five-year RS increased more strongly over time for the younger group leading to larger disparities between age groups with stage III or IV NSCLC. CONCLUSION: More curative-intent treatment and improved RS for NSCLC were seen over time, but were less profound among elderly. Disparities herein between age groups seemed to become smaller over time for stage I NSCLC, did not change for stage II, and were widening for stage III and IV at the expense of elderly. Future prospective studies should focus on optimizing treatment selection and outcomes for elderly.

Timed Get Up and Go Test and Geriatric 8 Scores and the Association With (Chemo-)Radiation Therapy Noncompliance and Acute Toxicity in Elderly Cancer Patients.

PURPOSE: To investigate whether the Geriatric 8 (G8) and the Timed Get Up and Go Test (TGUGT) and clinical and demographic patient characteristics were associated with acute toxicity of radiation therapy and noncompliance in elderly cancer patients being irradiated with curative intent. METHODS AND MATERIALS: Patients were eligible if aged ≥65 years and diagnosed with breast, non-small cell lung, prostate, head and neck, rectal, or esophageal cancer, and were referred for curative radiation therapy. We recorded acute toxicity and noncompliance and identified potential predictors, including the G8 and TGUGT. RESULTS: We investigated 402 patients with a median age of 72 years (range, 65-96 years). According to the G8, 44.4% of the patients were frail. Toxicity grade ≥3 was observed in 22% of patients who were frail according to the G8 and 9.1% of patients who were not frail. The difference was 13% (confidence interval 5.2%-20%; P=.0006). According to the TGUGT 18.8% of the patients were frail; 21% of the frail according to the TGUGT developed toxicity grade ≥3, compared with 13% who were not frail. The difference was 7.3% (confidence interval -2.7% to 17%; P=.11). Overall compliance was 95%. Toxicity was most strongly associated with type of primary tumor, chemotherapy, age, and World Health Organization performance status. Compliance was associated with type of primary tumor and age. CONCLUSIONS: The usefulness of the TGUGT and G8 score in daily practice seems to be limited. Type of primary tumor, chemoradiotherapy, age, and World Health Organization performance status were more strongly associated with acute toxicity. Only chemoradiotherapy and age were associated with noncompliance. Overall the compliance was very high. To allow better-informed treatment decisions, a more accurate prediction of toxicity is desirable.

PET imaging of zirconium-89 labelled cetuximab: A phase I trial in patients with head and neck and lung cancer.

BACKGROUND AND PURPOSE: PET imaging of cetuximab uptake may help selecting cancer patients with the highest chance of benefit. The aim of this phase I trial was to determine the safety of the tracer 89Zr-cetuximab and to assess tumour uptake. METHODS: Two dose schedules were used; two consecutive doses of 60MBq 89Zr-cetuximab or a single dose of 120MBq, both preceded by 400mg/m2 of unlabelled cetuximab. Toxicity (CTCAE 3.0) was scored twice weekly. PET-CT scans were acquired on days 4, 5 and 6 (step 1) or 5, 6, 7 (step 2). Because tumour uptake could not be assessed satisfactorily, a third step was added including EGFR overexpressing tumours. RESULTS: Nine patients were included (6 NSCLC; 3 HNC). No additional toxicity was associated with administration of 89Zr-cetuximab compared to standard cetuximab. A tumour to blood ratio (TBR)>1 was observed in all but one patient, with a maximum of 4.56. TBR was not different between dose schedules. There was a trend for higher TBR at intervals>5days after injection. CONCLUSIONS: Both presented 89Zr-cetuximab administration schedules are safe. The recommended dose for future trials is 60MBq, with a minimum time interval for scanning of 6days.