Dexamethasone for the Prevention of a Pain Flare After Palliative Radiation Therapy for Painful Bone Metastases: The Multicenter Double-Blind Placebo-Controlled 3-Armed Randomized Dutch DEXA Study.

PURPOSE: After radiation therapy for painful bone metastases, up to 44% of patients report a pain flare (PF). Our study compared 2 dose schedules of dexamethasone versus placebo to prevent PF. METHODS AND MATERIALS: This double-blind, randomized, placebo-controlled trial allocated patients with painful bone metastases from solid tumors randomly to receive 8 mg dexamethasone before radiation therapy followed by 3 daily doses (group A), 8 mg dexamethasone followed by 3 doses of placebo (group B), or 4 doses of placebo (group C). Patients reported worst pain scores, study medication side effects, and opioid intake before treatment and thereafter daily for 14 days and on day 28. PF was defined as at least a 2-point increase on a 0 to 10 pain scale with no decrease in opioid intake or a 25% or greater increase in opioid intake with no decrease in pain score, followed by a return to baseline or lower. The primary analysis was by intention to treat with patients who had missing data classified as having a PF. RESULTS: From January 2012 to April 2016, 295 patients were randomized. PF incidence was 38% for group A, 27% for group B, and 39% for group C (P = .07). Although patients in group B had the lowest PF incidence, a relatively high percentage did not return to baseline pain levels, indicating pain progression. The mean duration of PF was 2.1 days for group A, 4.5 days for group B, and 3.3 days for group C (P = .0567). Dexamethasone postponed PF occurrence; in group A 52% occurred on days 2 to 5 versus 73% in group B and 99% in group C (P = .02). Patients in group A reported lower mean pain scores on days 2 to 5 than those in group B or C (P < .001). Side effects were similar. CONCLUSIONS: There was insufficient evidence that dexamethasone reduced the incidence of radiation-induced PF. However, dexamethasone postponed the occurrence of PF and led to lower mean pain scores on days 2 to 5.

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.

Patterns of practice in palliative radiotherapy for bleeding tumours in the Netherlands; a survey study among radiation oncologists.

BACKGROUND AND PURPOSE: Palliative radiotherapy (RT) is one of the treatment options for bleeding tumours; a frequent symptom in patients with advanced cancer. The optimal RT schedule is however unclear. This study explores the current pattern of practice of palliative RT for bleeding tumours in the Netherlands. MATERIALS AND METHODS: An internet-based questionnaire, including respondent characteristics, factors influencing the choice of RT schedules and five patient case scenarios, was sent to all members of the Dutch Society for Radiation Oncology. Descriptive statistics were used to evaluate the results. RESULTS: The response rate was 125/374 (34%); representing 20 out of 21 Dutch RT departments. Most reported influencing factors were performance status, prognosis, patients' comfort and patients' choice. Most preferred RT schedules were 1 × 8 Gy for hematemesis, 1 × 8 Gy and 5 × 4 Gy for haemoptysis, 5 × 4 Gy for haematuria, 5 × 5 Gy for rectal bleeding, 1 × 8 Gy, 5 × 4 Gy and 10-13 × 3 Gy for vaginal bleeding. CONCLUSIONS: The current patterns of practice in the Netherlands for bleeding tumours varied considerably. Most often a single fraction is chosen (35% of all cases), followed by a five-fraction schedule (30% of all cases). The choice of an RT schedule is mainly influenced by patient related factors.

Contact of a tumour with the pleura is not associated with regional recurrence following stereotactic ablative radiotherapy for early stage non-small cell lung cancer.

BACKGROUND AND PURPOSE: The aim was to investigate the incidence of isolated regional failure following stereotactic ablative radiotherapy (SABR) and risk factors for recurrence. MATERIALS AND METHODS: Early stage non-small cell lung cancer (NSCLC) patients treated with SABR were included in this retrospective cohort study, with isolated regional recurrence (IRR) as primary endpoint, distant recurrence (DR) and overall survival (OS) as secondary endpoints. Survival analyses were performed using the cumulative incidence function (IRR and DR) or the Kaplan-Meier method (OS) and Cox proportional hazards modelling for univariate and multivariate analyses. The prognostic effect of contact between the tumour and the pleura was investigated using the CT scans used for SABR planning. RESULTS: A total of 554 patients were included, of whom 494 could be analysed for IRR. The median follow-up for surviving patients was 48.1 months. Twenty-one patients developed an IRR (4%). The cumulative incidence of IRR and DR after 1-, 2-, and 5 years was 2%, 3%, 7% and 8%, 15% and 21%, respectively. Two year OS was 71%. The presence and type of pleural contact was not associated with any of the studied outcomes. CONCLUSION: The presence, type and length of pleural contact as surrogate for visceral pleural invasion were not predictive for outcome. Further studies focussing on risk factors for occult nodal involvement, (I)RR, distant metastases and mortality in early stage NSCLC are warranted for the development of risk adapted diagnostic, treatment and follow-up strategies as more younger, operable and fitter patients receive SABR.

The impact of training and professional collaboration on the interobserver variation of lung cancer delineations: a multi-institutional study.

BACKGROUND: To assess the impact of training and interprofessional collaboration on the interobserver variation in the delineation of the lung gross tumor volume (GTVp) and lymph node (GTVln). MATERIAL AND METHODS: Eight target volume delineations courses were organized between 2008 and 2013. Specialists and trainees in radiation oncology were asked to delineate the GTVp and GTVln on four representative CT images of a patient diagnosed with lung cancer individually prior each course (baseline), together as group (interprofessional collaboration) and post-training. The mean delineated volume and local standard deviation (local SD) between the contours for each course group were calculated and compared with the expert delineations. RESULTS: A total 410 delineations were evaluated. The average local SD was lowest for the interprofessional collaboration (GTVp = 0.194 cm, GTVln = 0.371 cm) followed by the post-training (GTVp = 0.244 cm, GTVln = 0.607 cm) and baseline delineations (GTVp = 0.274 cm, GTVln: 0.718 cm). The mean delineated volume was smallest for the interprofessional (GTVp = 4.93 cm3, GTVln = 4.34 cm3) followed by the post-training (GTVp = 5.68 cm3, GTVln = 5.47 cm3) and baseline delineations (GTVp = 6.65 cm3, GTVln = 6.93 cm3). All delineations were larger than the expert for both GTVp and GTVln (p < .001). CONCLUSION: Our findings indicate that image interpretational differences can lead to large interobserver variation particularly when delineating the GTVln. Interprofessional collaboration was found to have the greatest impact on reducing interobserver variation in the delineation of the GTVln. This highlights the need to develop a clinical workflow so as to ensure that difficult cases are reviewed routinely by a second radiation oncologist or radiologist so as to minimize the risk of geographical tumor miss and unnecessary irradiation to normal tissue.

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.

A framework based on hidden Markov trees for multimodal PET/CT image co-segmentation.

PURPOSE: The purpose of this study was to investigate the use of a probabilistic quad-tree graph (hidden Markov tree, HMT) to provide fast computation, robustness and an interpretational framework for multimodality image processing and to evaluate this framework for single gross tumor target (GTV) delineation from both positron emission tomography (PET) and computed tomography (CT) images. METHODS: We exploited joint statistical dependencies between hidden states to handle the data stack using multi-observation, multi-resolution of HMT and Bayesian inference. This framework was applied to segmentation of lung tumors in PET/CT datasets taking into consideration simultaneously the CT and the PET image information. PET and CT images were considered using either the original voxels intensities, or after wavelet/contourlet enhancement. The Dice similarity coefficient (DSC), sensitivity (SE), positive predictive value (PPV) were used to assess the performance of the proposed approach on one simulated and 15 clinical PET/CT datasets of non-small cell lung cancer (NSCLC) cases. The surrogate of truth was a statistical consensus (obtained with the Simultaneous Truth and Performance Level Estimation algorithm) of three manual delineations performed by experts on fused PET/CT images. The proposed framework was applied to PET-only, CT-only and PET/CT datasets, and were compared to standard and improved fuzzy c-means (FCM) multimodal implementations. RESULTS: A high agreement with the consensus of manual delineations was observed when using both PET and CT images. Contourlet-based HMT led to the best results with a DSC of 0.92 ± 0.11 compared to 0.89 ± 0.13 and 0.90 ± 0.12 for Intensity-based HMT and Wavelet-based HMT, respectively. Considering PET or CT only in the HMT led to much lower accuracy. Standard and improved FCM led to comparatively lower accuracy than HMT, even when considering multimodal implementations. CONCLUSIONS: We evaluated the accuracy of the proposed HMT-based framework for PET/CT image segmentation. The proposed method reached good accuracy, especially with pre-processing in the contourlet domain.

Nodal recurrence after stereotactic body radiotherapy for early stage non-small cell lung cancer: Incidence and proposed risk factors.

Stereotactic body radiotherapy (SBRT) is an alternative to surgery for patients with early stage non-small cell lung cancer (NSCLC) who are inoperable due to comorbid disease or who refuse surgery. SBRT results in an excellent local control rate of more than 90%, which is comparable to surgery, while short and long-term overall toxicity is low. Surgically treated patients are often more extensively staged pre-operatively, e.g. with endobronchial ultrasound and/or mediastinoscopy, and typically undergo intra-operative lymph node dissection or sampling. Occult nodal metastases (ONM), detected by lymph node dissection, have been shown to increase the incidence of regional recurrence (RR) after surgery, which is associated with poor outcome. In patients undergoing SBRT, however, definite pathological nodal staging is lacking and so other ways to identify patients at high risk for ONM and RR are desirable. The aim of this systematic review is to summarize the incidence of, and risk factors for, RR after SBRT and compare these to those after surgery. The available evidence shows the incidence of RR after SBRT or surgery to be comparable, despite more elaborate pre- and intra-operative lymph node evaluation in surgical patients. However, the fact that this finding is based on mostly retrospective studies in which the majority of patients treated with SBRT were inoperable, needs to be taken into consideration. For now, there is no evidence that inoperable clinical stage I patients with no indication of pathological lymph nodes on PET/CT will benefit from more invasive lymph node staging prior to SBRT.

Is selective nodal irradiation in non-small cell lung cancer still safe when using IMRT? Results of a prospective cohort study.

BACKGROUND AND PURPOSE: Isolated nodal failures (INF) are rare after 3D-conformal radiotherapy (3D-CRT) for stage III non-small cell lung cancer (NSCLC). Since incidental nodal irradiation doses are lower with Intensity Modulated Radiation Therapy (IMRT) than with 3D-CRT, INF may be higher after IMRT. We therefore investigated the incidence of INF after IMRT in stage III NSCLC patients. MATERIALS AND METHODS: Stage III NSCLC patients undergoing radical radiotherapy using IMRT in the period January 2010 till March 2012 were included. The primary endpoint was the rate of INF, secondary endpoints included patterns of failure, progression free survival (PFS), overall survival (OS) and toxicity. RESULTS: 183 stage III NSCLC patients were enrolled. With a median follow-up of 58.0months 2.2% of patients had an INF. The median PFS was 15.0months, the median OS 19.5months. Patterns of recurrence: 2.2% INF, 11.5% local and 2.7% loco-regional recurrence, 26.8% distant metastases only, 18.0% a combination of local/loco-regional and distant metastases, and 38.3% patients without recurrence. One INF was out of field, in adjacent lymph nodes. Acute toxicity was limited. DISCUSSION: Selective nodal irradiation using IMRT in stage III NSCLC patients results in a low in-field incidence of INF (2.2%), similar to 3D-CRT, and may thus be considered safe.

Selective mediastinal node irradiation in non-small cell lung cancer in the IMRT/VMAT era: How to use E(B)US-NA information in addition to PET-CT for delineation?

BACKGROUND: FDG-PET-CT-based selective lymph node (LN) irradiation is standard using 3D-conformal techniques for locally advanced NSCLC. With newer techniques (intensity-modulated/volumetric-arc therapy (IMRT/VMAT)), the dose to non-involved adjacent LN decreases, which raises the question whether FDG-PET-CT-delineation is still safe. We therefore evaluated the impact of adding linear endosonography with needle aspiration (E(B)US-NA) to FDG-PET-CT in selective nodal irradiation. METHODS: Based on literature data on sensitivity and specificity of E(B)US-NA in FDG-PET-CT-staged NSCLC, false negative (FN) rates for different constellations of CT, PET and E(B)US-NA were calculated. The algorithm was tested on consecutive patients with N2/N3 disease referred for radiotherapy in Leuven and Maastricht. RESULTS: An algorithm determining when to include LN in the GTV is proposed, based on data from 5 meta-analyses. Adding E(B)US-NA to FDG-PET-CT decreases the FN-rate, but for PET-positive and E(B)US-negative LN, FN rates are still 14-16%. In Leuven 520 LN were analyzed, in Maastricht 364 LN; with E(B)US-NA a geographical miss was avoided in 2 (2/40=5%) and 1 (1/28=4%) patients, respectively. CONCLUSIONS: E(B)US-NA in addition to FDG-PET-CT for mediastinal staging decreases the risk of a geographical miss with 4-5%. The impact of this small decrease on survival is unknown. The proposed algorithm may guide the radiation oncologist when to include LN in the nodal GTV.

Primary tumour standardised uptake value is prognostic in nonsmall cell lung cancer: a multivariate pooled analysis of individual data.

(18)F-fluoro-2-deoxy-d-glucose positron emission tomography (PET) complements conventional imaging for diagnosing and staging lung cancer. Two literature-based meta-analyses suggest that maximum standardised uptake value (SUVmax) on PET has univariate prognostic value in nonsmall cell lung cancer (NSCLC). We analysed individual data pooled from 12 studies to assess the independent prognostic value of binary SUVmax for overall survival.After searching the published literature and identifying unpublished data, study coordinators were contacted and requested to provide data on individual patients. Cox regression models stratified for study were used.Data were collected for 1526 patients (median age 64 years, 60% male, 34% squamous cell carcinoma, 47% adenocarcinoma, 58% stage I-II). The combined univariate hazard ratio for SUVmax was 1.43 (95% CI 1.22-1.66) and nearly identical if the SUV threshold was calculated stratifying for histology. Multivariate analysis of patients with stage I-III disease identified age, stage, tumour size and receipt of surgery as independent prognostic factors; adding SUV (HR 1.58, 95% CI 1.27-1.96) improved the model significantly. The only detected interaction was between SUV and stage IV disease.SUV seems to have independent prognostic value in stage I-III NSCLC, for squamous cell carcinoma and for adenocarcinoma.

Set-up verification and 2-dimensional electronic portal imaging device dosimetry during breath hold compared with free breathing in breast cancer radiation therapy.

PURPOSE: To compare set-up and 2-dimensional (2D) electronic portal imaging device (EPID) dosimetry data of breast cancer patients treated during voluntary moderately deep inspiration breath hold (vmDIBH) and free breathing (FB). METHODS AND MATERIALS: Set-up data were analyzed for 29 and 51 consecutively treated patients, irradiated during FB and vmDIBH, respectively. Of the 51 vmDIBH patients, the first 25 had undergone an extra trained computed tomography (CT) scan and used an additional "breathing stick" (vmDIBH_trained). The last 26 patients did not use the breathing stick and did not undergo a trained CT (vmDIBH_untrained). The delivered 2D transit dose was measured with EPID in 15 FB and 28 vmDIBH patients and compared with a 2D predicted dose by calculating global gamma values γ using 5% and 5 mm as dose difference and distance-to-agreement criteria, respectively. Measurements with a percentage of pixels with an absolute gamma value > 1 (|γ| > 1) greater than 10% were classified as deviating. RESULTS: Only small, sub-millimeter differences were seen in the set-up data between the different patient groups. The mean of means, systematic error, and random error ranged from - 0.6 mm to 3.3 mm. The percentage of pixels with |γ| > 1 for all patients was 9.8% (2-25.8). No statistically significant differences were observed between the patient groups. In total, 38% of the gamma images were classified as deviating: 43.6% in vmDIBH_untrained patients compared with 38.0% in vmDIBH_trained patients and 33.3% in FB patients (P > .05). CONCLUSION: Both set-up and 2D EPID dosimetry data indicate that reproducibility of radiation therapy for patients treated during FB and vmDIBH is similar. Small but not significant differences in 2D EPID dosimetry were observed. Further investigation with 3-dimensional EPID dosimetry is recommended to investigate the clinical relevance of deviant gamma images.

'Reconstruction: before or after postmastectomy radiotherapy?' A systematic review of the literature.

OBJECTIVE: The aim of this review is to investigate the effect of timing of the reconstruction and radiotherapy, with respect to complication rate and cosmetic outcome, with a special focus on the timing of the placement of the definite implant. METHODS: PubMed was searched for publications between January 2000 and December 2012. Of 37 eligible studies, timing of reconstruction, type, and incidence of complications were recorded. First, we calculated the weighted mean including confidence intervals for complications and cosmetic outcome overall, and for the following subgroups: (1) Autologous reconstruction after radiotherapy; (2) Definite implant reconstruction after radiotherapy; (3) Autologous reconstruction before radiotherapy; (4) Definite implant reconstruction before radiotherapy. A second analysis was performed using only studies that directly compared group 1 versus 3 and 2 versus 4. RESULTS: A large variation in complication rates (8.7-70.0%) and in acceptable cosmetic outcome (41.4-93.3%) was reported. The first analysis showed more complications and a higher revision rate if an implant reconstruction was performed after radiotherapy; for autologous reconstruction fibrosis occurred more often if reconstruction was applied first. The second analysis showed no significant differences in total complication rate. Only implant failure occurred more often if applied after radiotherapy (odds ratio (OR) 3.03 [1.59-5.77]). No differences were found in both patient and physician satisfaction. CONCLUSIONS: A definite implant reconstruction placed before radiotherapy limits the rate of complications. For autologous reconstruction, less fibrosis is seen if reconstruction is performed after radiotherapy, but timing had no significant impact on total complication rate.

A prospective study comparing the predictions of doctors versus models for treatment outcome of lung cancer patients: a step toward individualized care and shared decision making.

BACKGROUND: Decision Support Systems, based on statistical prediction models, have the potential to change the way medicine is being practiced, but their application is currently hampered by the astonishing lack of impact studies. Showing the theoretical benefit of using these models could stimulate conductance of such studies. In addition, it would pave the way for developing more advanced models, based on genomics, proteomics and imaging information, to further improve the performance of the models. PURPOSE: In this prospective single-center study, previously developed and validated statistical models were used to predict the two-year survival (2yrS), dyspnea (DPN), and dysphagia (DPH) outcomes for lung cancer patients treated with chemo radiation. These predictions were compared to probabilities provided by doctors and guideline-based recommendations currently used. We hypothesized that model predictions would significantly outperform predictions from doctors. MATERIALS AND METHODS: Experienced radiation oncologists (ROs) predicted all outcomes at two timepoints: (1) after the first consultation of the patient, and (2) after the radiation treatment plan was made. Differences in the performances of doctors and models were assessed using Area Under the Curve (AUC) analysis. RESULTS: A total number of 155 patients were included. At timepoint #1 the differences in AUCs between the ROs and the models were 0.15, 0.17, and 0.20 (for 2yrS, DPN, and DPH, respectively), with p-values of 0.02, 0.07, and 0.03. Comparable differences at timepoint #2 were not statistically significant due to the limited number of patients. Comparison to guideline-based recommendations also favored the models. CONCLUSION: The models substantially outperformed ROs' predictions and guideline-based recommendations currently used in clinical practice. Identification of risk groups on the basis of the models facilitates individualized treatment, and should be further investigated in clinical impact studies.

A phase I study of concurrent individualized, isotoxic accelerated radiotherapy and cisplatin-vinorelbine-cetuximab in patients with stage III non-small-cell lung cancer.

BACKGROUND: In this open-label phase I study, the maximum-tolerated dose of cetuximab with concurrent chemoradiotherapy (C-CRT) in stage III non-small-cell lung cancer together with individualized, isotoxic accelerated radiotherapy (RT) was investigated. METHODS: Patients with stage III non-small-cell lung cancer, World Health Organization performance status 0-1, forced expiratory volume in 1 second more than 50%, carbon monoxide diffusing capacity more than 50%, weight loss less than 10%, and no severe comorbidity were enrolled. Patients without progression after one to two cycles of gemcitabine-carboplatin were included and treated with cetuximab 400 mg/kg d7 and 250 mg/kg weekly together with RT and cisplatin (50 mg/m d1, 8; 40 mg/m d22)-vinorelbine for 5 weeks. Vinorelbine was escalated in three steps; (1) 10 mg/m d1, 8 and 8 mg/m d22, 29; (2) 20 mg/m d1, 8 and 8 mg/m d22, 29; (3) 20 mg/m d1, 8; 15 mg/m d22, 29. An individualized prescribed RT dose based on normal tissue dose constraints was applied (e.g., mean lung dose 19 Gy). The primary endpoint was the maximum-tolerated dose 3 months after the end of C-CRT; secondary endpoints were toxicity and metabolic response as assessed by positron emission tomography. RESULTS: Between September 2007 and October 2010, 25 patients (12 men, 13 women, mean age 59 years) were included. The mean RT dose was 62 ± 6.6 Gy. The vinorelbine dose could be escalated to dose level 3. Twelve of 25 patients experienced greater than or equal to grade 3 toxicity (esophagitis 3, rash 1, diarrhea 1, cough 1, dyspnea 1, vomiting 1, and pulmonary embolism 1). No dose-limiting toxicities were observed. One patient with a complete pathological response in dose level 3 developed a fatal hemoptysis 4 months after RT. Metabolic remissions were observed in 19 of 22 patients. CONCLUSION: C-CRT with cetuximab and cisplatin-vinorelbine is safe to deliver at full dose. The recommended phase II dose is therefore cetuximab 400 mg/m d7 and 250 mg/m weekly, cisplatin 50 mg/m d1, 8; 40 mg/m d22 and vinorelbine 20 mg/m d1, 8; 15 mg/m d22, 29 for 5 weeks together with RT.

Long-term survival of stage T4N0-1 and single station IIIA-N2 NSCLC patients treated with definitive chemo-radiotherapy using individualised isotoxic accelerated radiotherapy (INDAR).

BACKGROUND: Non-small cell lung cancer (NSCLC) stage T4N0-1 or single nodal station IIIA-N2 are two stage III sub-groups for which the outcome of non-surgical therapy is not well known. We investigated the results of individualised isotoxic accelerated radiotherapy (INDAR) and chemotherapy in this setting. METHODS: Analysis of NSCLC patients included in 2 prospective trials (NCT00573040 and NCT00572325) stage T4N0-1 or IIIA-N2 with 1 pathologic nodal station, treated with chemo-radiotherapy (CRT) using INDAR with concurrent or sequential platinum-based chemotherapy. Overall survival (OS) was updated and calculated from date of diagnosis (Kaplan-Meier). Toxicity was scored following CTCAEv3.0. To allow comparison with other articles the subgroups were also analysed separately for toxicity, progression free and overall survival. RESULTS: 83 patients (42 T4N0-1 and 41 IIIA-N2) were identified: the median radiotherapy dose was 65Gy. Thirty-seven percent of patients received sequential CRT and 63% received concurrent CRT. At a median follow-up of 48 months the median OS for T4N0-1 patients was 34 months with 55% 2-year survival and 25% 5-year survival. For stage IIIA-N2 at a median follow-up of 50 months the median OS was 26 months with 2- and 5-year survival rates of 53% and 24%, respectively. CONCLUSION: Chemo-radiation using INDAR yields promising survival results in patients with single-station stage IIIA-N2 or T4N0-1 NSCLC.

Volumetric CT-based segmentation of NSCLC using 3D-Slicer.

Accurate volumetric assessment in non-small cell lung cancer (NSCLC) is critical for adequately informing treatments. In this study we assessed the clinical relevance of a semiautomatic computed tomography (CT)-based segmentation method using the competitive region-growing based algorithm, implemented in the free and public available 3D-Slicer software platform. We compared the 3D-Slicer segmented volumes by three independent observers, who segmented the primary tumour of 20 NSCLC patients twice, to manual slice-by-slice delineations of five physicians. Furthermore, we compared all tumour contours to the macroscopic diameter of the tumour in pathology, considered as the "gold standard". The 3D-Slicer segmented volumes demonstrated high agreement (overlap fractions > 0.90), lower volume variability (p = 0.0003) and smaller uncertainty areas (p = 0.0002), compared to manual slice-by-slice delineations. Furthermore, 3D-Slicer segmentations showed a strong correlation to pathology (r = 0.89, 95%CI, 0.81-0.94). Our results show that semiautomatic 3D-Slicer segmentations can be used for accurate contouring and are more stable than manual delineations. Therefore, 3D-Slicer can be employed as a starting point for treatment decisions or for high-throughput data mining research, such as Radiomics, where manual delineating often represent a time-consuming bottleneck.

Hypoxia imaging with [¹8F]HX4 PET in NSCLC patients: defining optimal imaging parameters.

BACKGROUND AND PURPOSE: [(18)F]HX4 is a promising hypoxia PET-tracer. Uptake, spatio-temporal stability and optimal acquisition parameters for [(18)F]HX4 PET imaging were evaluated in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: [(18)F]HX4 PET/CT images of 15 NSCLC patients were acquired 2h and 4h after injection (p.i.). Maximum standardized-uptake-value (SUV(max)), tumor-to-blood-ratio (TBR(max)), hypoxic fraction (HF) and contrast-to-noise-ratio (CNR) were determined for all lesions. To evaluate spatio-temporal stability, DICE-similarity and Pearson correlation coefficients were calculated. Optimal acquisition-duration was assessed by comparing 30, 20, 10 and 5 min acquisitions. RESULTS: Considerable uptake (TBR >1.4) was observed in 18/25 target lesions. TBR(max) increased significantly from 2 h (1.6 ± 0.3) to 4 h p.i. (2.0 ± 0.6). Uptake patterns at 2 h and 4 h p.i. showed a strong correlation (R=0.77 ± 0.10) with a DICE similarity coefficient of 0.69 ± 0.08 for the 30% highest uptake volume. Reducing acquisition-time resulted in significant changes in SUV(max) and CNR. TBR(max) and HF were only affected for scan-times of 5 min. CONCLUSIONS: The majority of NSCLC lesions showed considerable [(18)F]HX4 uptake. The heterogeneous uptake pattern was stable between 2 h and 4 h p.i. [(18)F]HX4 PET imaging at 4 h p.i. is superior to 2 h p.i. to reach highest contrast. Acquisition time may be reduced to 10 min without significant effects on TBR(max) and HF.

Cardiac comorbidity is an independent risk factor for radiation-induced lung toxicity in lung cancer patients.

PURPOSE: To test the hypothesis that cardiac comorbidity before the start of radiotherapy (RT) is associated with an increased risk of radiation-induced lung toxicity (RILT) in lung cancer patients. MATERIAL AND METHODS: A retrospective analysis was performed of a prospective cohort of 259 patients with locoregional lung cancer treated with definitive radio(chemo)therapy between 2007 and 2011 (ClinicalTrials.gov Identifiers: NCT00572325 and NCT00573040). We defined RILT as dyspnea CTCv.3.0 grade ≥2 within 6 months after RT, and cardiac comorbidity as a recorded treatment of a cardiac pathology at a cardiology department. Univariate and multivariate analyses, as well as external validation, were performed. The model-performance measure was the area under the receiver operating characteristic curve (AUC). RESULTS: Prior to RT, 75/259 (28.9%) patients had cardiac comorbidity, 44% of whom (33/75) developed RILT. The odds ratio of developing RILT for patients with cardiac comorbidity was 2.58 (p<0.01). The cross-validated AUC of a model with cardiac comorbidity, tumor location, forced expiratory volume in 1s, sequential chemotherapy and pretreatment dyspnea score was 0.72 (p<0.001) on the training set, and 0.67 (p<0.001) on the validation set. CONCLUSION: Cardiac comorbidity is an important risk factor for developing RILT after definite radio(chemo)therapy of lung cancer patients.