Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study.

Introduction: It is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart. Methods: Treatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping. Results: The population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24-29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04-1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84-1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume. Conclusions: Besides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose-sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.

Early radiologic and metabolic tumour response assessment during combined chemo-radiotherapy for locally advanced NSCLC.

Background: The role of early treatment response for patients with locally advanced non-small cell lung cancer (LA-NSCLC) treated with concurrent chemo-radiotherapy (cCRT) is unclear. The study aims to investigate the predictive value of response to induction chemotherapy (iCX) and the correlation with pattern of failure (PoF). Materials and methods: Patients with LA-NSCLC treated with cCRT were included for analyses (n = 276). Target delineations were registered from radiotherapy planning PET/CT to diagnostic PET/CT, in between which patients received iCX. Volume, sphericity, and SUVpeak were extracted from each scan. First site of failure was categorised as loco-regional (LR), distant (DM), or simultaneous LR+M (LR+M). Fine and Gray models for PoF were performed: a baseline model (including performance status (PS), stage, and histology), an image model for squamous cell carcinoma (SCC), and an image model for non-SCC. Parameters included PS, volume (VOL) of tumour, VOL of lymph nodes, ΔVOL, sphericity, SUVpeak, ΔSUVpeak, and oligometastatic disease. Results: Median follow-up was 7.6 years. SCC had higher sub-distribution hazard ratio (sHR) for LRF (sHR = 2.771 [1.577:4.87], p < 0.01) and decreased sHR for DM (sHR = 0.247 [0.125:0.485], p  <  0.01). For both image models, high diagnostic SUVpeak increased risk of LRF (sHR = 1.059 [1.05:1.106], p < 0.01 for SCC, sHR = 1.12 [1.03:1.21], p < 0.01 for non-SCC). Patients with SCC and less decrease in VOL had higher sHR for DM (sHR = 1.025[1.001:1.048] pr. % increase, p = 0.038). Conclusion: Poor response in disease volume was correlated with higher sHR of DM for SCC, no other clear correlation of response and PoF was observed. Histology significantly correlated with PoF with SCC prone to LRF and non-SCC prone to DM as first site of failure. High SUVpeak at diagnosis increased the risk of LRF for both histologies.

An open source auto-segmentation algorithm for delineating heart and substructures - Development and validation within a multicenter lung cancer cohort.

BACKGROUND AND PURPOSE: Irradiation of the heart in thoracic cancers raises toxicity concerns. For accurate dose estimation, automated heart and substructure segmentation is potentially useful. In this study, a hybrid automatic segmentation is developed. The accuracy of delineation and dose predictions were evaluated, testing the method's potential within heart toxicity studies. MATERIALS AND METHODS: The hybrid segmentation method delineated the heart, four chambers, three large vessels, and the coronary arteries. The method consisted of a nnU-net heart segmentation and partly atlas- and model-based segmentation of the substructures. The nnU-net training and atlas segmentation was based on lung cancer patients and was validated against a national consensus dataset of 12 patients with breast cancer. The accuracy of dose predictions between manual and auto-segmented heart and substructures was evaluated by transferring the dose distribution of 240 previously treated lung cancer patients to the consensus data set. RESULTS: The hybrid auto-segmentation method performed well with a heart dice similarity coefficient (DSC) of 0.95, with no statistically significant difference between the automatic and manual delineations. The DSC for the chambers varied from 0.78-0.86 for the automatic segmentation and was comparable with the inter-observer variability. Most importantly, the automatic segmentation was as precise as the clinical experts in predicting the dose distribution to the heart and all substructures. CONCLUSION: The hybrid segmentation method performed well in delineating the heart and substructures. The prediction of dose by the automatic segmentation was aligned with the manual delineations, enabling measurement of heart and substructure dose in large cohorts. The delineation algorithm will be available for download.

Different benefits of adaptive radiotherapy for different histologies of NSCLC.

BACKGROUND: Adenocarcinoma (AC) and squamous cell carcinoma (SCC) are the most frequent histological subtypes of non-small cell lung cancer (NSCLC). The aim of this study was to investigate how patients with AC and SCC benefit from image-guided adaptive radiotherapy (ART) with tumour match. MATERIAL AND METHODS: Consecutive patients diagnosed with AC or SCC of the lung treated with definitive chemo-radiotherapy before and after the implementation of ART and tumour match were retrospectively included for analyses. Data collection included baseline patient and treatment characteristics in addition to clinical data on radiation pneumonitis (RP), failure, and survival. Patients were divided into four categories based on their histology and treatment before (n = 173 [89 AC and 84 SCC]) and after implementation of ART (n = 240 [141 AC and 99 SCC]). RESULTS: Median follow-up was 5.7 years for AC and 6.3 years for SCC. Mean lung dose decreased for both histologies with ART, whereas mean heart dose only decreased for patients with AC. Incidences of grade 3 and 5 RP decreased for both histologies with ART. Loco-regional failure (LRF) rates decreased significantly for patients with SCC after ART (p = .04), no significant difference was observed for AC. Overall survival (OS) increased significantly for SCC after ART (p < .01): the 2-year OS increased from 31.0% (95% confidence interval [CI] [22.5-42.6]) to 54.5% (95% CI [45.6-65.3]). No significant effect on OS was observed for patients with AC. CONCLUSION: ART and tumour match in the radiotherapeutic treatment of patients with locally advanced NSCLC primarily led to decreased LRF and improved OS for patients with SCC.

Refining critical structure contouring in STereotactic Arrhythmia Radioablation (STAR): Benchmark results and consensus guidelines from the STOPSTORM.eu consortium.

BACKGROUND AND PURPOSE: In patients with recurrent ventricular tachycardia (VT), STereotactic Arrhythmia Radioablation (STAR) shows promising results. The STOPSTORM.eu consortium was established to investigate and harmonise STAR treatment in Europe. The primary goals of this benchmark study were to standardise contouring of organs at risk (OAR) for STAR, including detailed substructures of the heart, and accredit each participating centre. MATERIALS AND METHODS: Centres within the STOPSTORM.eu consortium were asked to delineate 31 OAR in three STAR cases. Delineation was reviewed by the consortium expert panel and after a dedicated workshop feedback and accreditation was provided to all participants. Further quantitative analysis was performed by calculating DICE similarity coefficients (DSC), median distance to agreement (MDA), and 95th percentile distance to agreement (HD95). RESULTS: Twenty centres participated in this study. Based on DSC, MDA and HD95, the delineations of well-known OAR in radiotherapy were similar, such as lungs (median DSC = 0.96, median MDA = 0.1 mm and median HD95 = 1.1 mm) and aorta (median DSC = 0.90, median MDA = 0.1 mm and median HD95 = 1.5 mm). Some centres did not include the gastro-oesophageal junction, leading to differences in stomach and oesophagus delineations. For cardiac substructures, such as chambers (median DSC = 0.83, median MDA = 0.2 mm and median HD95 = 0.5 mm), valves (median DSC = 0.16, median MDA = 4.6 mm and median HD95 = 16.0 mm), coronary arteries (median DSC = 0.4, median MDA = 0.7 mm and median HD95 = 8.3 mm) and the sinoatrial and atrioventricular nodes (median DSC = 0.29, median MDA = 4.4 mm and median HD95 = 11.4 mm), deviations between centres occurred more frequently. After the dedicated workshop all centres were accredited and contouring consensus guidelines for STAR were established. CONCLUSION: This STOPSTORM multi-centre critical structure contouring benchmark study showed high agreement for standard radiotherapy OAR. However, for cardiac substructures larger disagreement in contouring occurred, which may have significant impact on STAR treatment planning and dosimetry evaluation. To standardize OAR contouring, consensus guidelines for critical structure contouring in STAR were established.

Expanded HILUS Trial: A Pooled Analysis of Risk Factors for Toxicity From Stereotactic Body Radiation Therapy of Central and Ultracentral Lung Tumors.

PURPOSE: Stereotactic body radiation therapy for tumors near the central airways implies high-grade toxic effects, as concluded from the HILUS trial. However, the small sample size and relatively few events limited the statistical power of the study. We therefore pooled data from the prospective HILUS trial with retrospective data from patients in the Nordic countries treated outside the prospective study to evaluate toxicity and risk factors for high-grade toxic effects. METHODS AND MATERIALS: All patients were treated with 56 Gy in 8 fractions. Tumors within 2 cm of the trachea, the mainstem bronchi, the intermediate bronchus, or the lobar bronchi were included. The primary endpoint was toxicity, and the secondary endpoints were local control and overall survival. Clinical and dosimetric risk factors were analyzed for treatment-related fatal toxicity in univariable and multivariable Cox regression analyses. RESULTS: Of 230 patients evaluated, grade 5 toxicity developed in 30 patients (13%), of whom 20 patients had fatal bronchopulmonary bleeding. The multivariable analysis revealed tumor compression of the tracheobronchial tree and maximum dose to the mainstem or intermediate bronchus as significant risk factors for grade 5 bleeding and grade 5 toxicity. The 3-year local control and overall survival rates were 84% (95% CI, 80%-90%) and 40% (95% CI, 34%-47%), respectively. CONCLUSIONS: Tumor compression of the tracheobronchial tree and high maximum dose to the mainstem or intermediate bronchus increase the risk of fatal toxicity after stereotactic body radiation therapy in 8 fractions for central lung tumors. Similar dose constraints should be applied to the intermediate bronchus as to the mainstem bronchi.

Local disease control after stereotactic body radiotherapy in patients with neuroendocrine neoplasms: a cohort study.

BACKGROUND: Neuroendocrine neoplasms represent a diverse group of malignancies. Anatomic origin, histology and aggressiveness vary extensively, from low-grade tumours with an indolent prognosis to highly aggressive conditions with poor outcome. Surgery, with a curative intent, is the standard of treatment when possible. Other treatment regimens include local treatment, or systemic therapy. The role of radiotherapy in treating neuroendocrine neoplasms is not yet established, but studies indicate that a high rate of local control can be achieved by high-dose radiotherapy. Stereotactic body radiotherapy (SBRT) is high dose of radiation delivered to a small volume. We aimed to investigate the one-year local control rate of SBRT in patients with neuroendocrine neoplasms. MATERIAL AND METHODS: Patients with neuroendocrine neoplasms treated with SBRT between 2003 and 2021 were retrospectively identified. Patient characteristics and SBRT-details were collected by review of patient records and the radiotherapy planning charts. All types except for small cell lung cancer and brain metastases were allowed. The prescribed dose was 45-67.8 Gy in three fractions. Progression, both within the target-site and in other sites, was determined based on existing imaging reports. One-year local control rate and systemic control rate was calculated. Descriptive analyses of local response duration, progression-free survival and overall survival were performed. RESULTS: Twenty-one patients were included. The one-year local control rate was 94%. Four of the patients had local progression. All patients receiving SBRT towards their primary tumour (n = 11) had a bronchopulmonary neuroendocrine neoplasm, and a one-year local control rate of 100%. In patients treated at a metastatic target, 80% developed systemic progression but the local control remained high. CONCLUSION: Our study suggests that SBRT may offer a feasible and effective treatment of neuroendocrine neoplasms in selected cases. SBRT provides long-term local stability and may be useful in treating patients with localised disease not fit for surgery.

Does coronary artery calcium score have an impact on overall survival for locally advanced non-small cell lung cancer treated with definitive radiotherapy.

BACKGROUND AND PURPOSE: Coronary artery calcium score (CACs) is an excellent marker for survival in non-cancer patients, but its role in locally advanced non-small cell lung cancer (LA-NSCLC) patients remains uncertain. In this study, we hypothesize that CACs is a prognostic marker for survival in a competing risk analysis in LA-NSCLC patients treated with definitive radiotherapy. MATERIALS AND METHODS: We included 644 patients with LA-NSCLC treated in 2014-2015 in Denmark. Baseline patient characteristics were derived from the Danish Lung Cancer Registry. Radiotherapy planning CT scans were used for manual CACs measurements, and the patients were divided into four groups, CACs 0, 1-99, 100-399, and ≥400. A multivariable Cox model utilizing bootstrapping for cross-validation modeled overall survival (OS). RESULTS: The median follow-up time was seven years, and the median OS was 26 months (95% CI 24-29). Within each CAC group 0, 1-99, 100-399, and ≥400 were 172, 182, 143, and 147 patients, respectively. In the univariable analysis, the survival decreased with increasing CACs. However, after adjustment for age, PS, radiotherapy dose, and logarithmic GTV, CACs did not have a statistically significant impact on OS with hazard ratios of 1.04 (95% CI 0.85-1.28), 1.11 (95%CI 0.89-1.43), and 1.16 (95%CI 0.92-1.47) for CACs 1-99, CACs 100-399 and ≥400, respectively. Elevated CACs was observed in 73 % of the patients suggesting a high risk of cardiac comorbidity before radiotherapy. CONCLUSION: CACs did not add prognostic information to our population's classical risk factors, such as tumor volume, performance status, and age; the lung cancer has the highest priority despite the risk of baseline cardiac comorbidity.

Survival benefits for non-small cell lung cancer patients treated with adaptive radiotherapy.

INTRODUCTION: Tumor match and adaptive radiotherapy based on on-treatment imaging increases the precision of RT. This allows a reduction of treatment volume and, consequently, of the dose to organs at risk. We investigate the clinical benefits of tumor match and adaptive radiotherapy for a cohort of non-small cell lung cancer patients (NSCLC). METHODS: In 2013, tumor match and adaptive radiotherapy based on daily cone-beam CT scans was introduced to ensure adaption of the radiotherapy treatment plan for all patients with significant anatomical changes during radiotherapy. Before 2013, the daily cone-beam CT scans were matched on the vertebra and anatomical changes were not evaluated systematically. To estimate the effect of tumor match and adaptive radiotherapy, 439 consecutive NSCLC patients treated with definitive chemo-radiotherapy (50-66 Gy/25-33 fractions, 2010-2018) were investigated retrospectively. They were split in two groups, pre-ART (before tumor match and adaptive radiotherapy, 184 patients), and ART (after tumor match and adaptive radiotherapy, 255 patients) and compared with respect to clinical, treatment-specific and dosimetric variables (χ2 tests, Mann Whitney U tests), progression, survival and radiation pneumonits (CTCAEv3). Progression-free and overall survival as well as radiation pneumonitis were compared with log-rank tests. Hazard ratios were estimated from Cox proportional hazard regression. RESULTS: No significant differences in stage (p = 0.36), histology (p = 0.35), PS (p = 0.12) and GTV volumes (p = 0.24) were observed. Concomitant chemotherapy was administered more frequently in the ART group (78%) compared to preART (64%), p < 0.001. Median[range] PTV volumes decreased from 456 [71;1262] cm3 (preART) to 270 [31;1166] cm3 (ART), p < 0.001, thereby significantly reducing mean doses to lungs (median, preART 16.4 [1.9;24.7] Gy, ART 12.1 [1.7;19.4] Gy, p < 0.001) and heart (median, preART 8.0 [0.1;32.1] Gy, ART 4.4 [0.1;33.9] Gy, p < 0.001). The incidence of RP at nine months decreased significantly with ART (50% to 20% for symptomatic RP (≥G2), 21% to 7% for severe RP (≥G3), 6% to 0.4% for lethal RP (G5), all p < 0.001). The two-year progression free survival increased from 22% (preART) to 30% (ART), while the overall survival increased from 43% (preART) to 56% (ART). The median overall survival time increased from 20 (preART) to 28 months (ART). CONCLUSION: Tumor match and adaptive radiotherapy significantly decreased radiation pneumonitis, while maintaining loco-regional control. Further, we observed a significantly improved progression-free and overall survival.

Personal innovative approach in radiation therapy of lung cancer- functional lung avoidance SPECT-guided (ASPECT) radiation therapy: a study protocol for phase II randomised double-blind clinical trial.

BACKGROUND: Radiation therapy (RT) plays a key role in curative-intent treatment for locally advanced lung cancer. Radiation induced pulmonary toxicity can be significant for some patients and becomes a limiting factor for radiation dose, suitability for treatment, as well as post treatment quality of life and suitability for the newly introduced adjuvant immunotherapy. Modern RT techniques aim to minimise the radiation dose to the lungs, without accounting for regional distribution of lung function. Many lung cancer patients have significant regional differences in pulmonary function due to smoking and chronic lung co-morbidity. Even though reduction of dose to functional lung has shown to be feasible, the method of preferential functional lung avoidance has not been investigated in a randomised clinical trial. METHODS: In this study, single photon emission computed tomography (SPECT/CT) imaging technique is used for functional lung definition, in conjunction with advanced radiation dose delivery method in randomised, double-blind trial. The study aims to assess the impact of functional lung avoidance technique on pulmonary toxicity and quality of life in patients receiving chemo-RT for lung cancer. Eligibility criteria are biopsy verified lung cancer, scheduled to receive (chemo)-RT with curative intent. Every patient will undergo a pre-treatment perfusion SPECT/CT to identify functional lung. At radiation dose planning, two plans will be produced for all patients on trial. Standard reference plan, without the use of SPECT imaging data, and functional avoidance plan, will be optimised to reduce the dose to functional lung within the predefined constraints. Both plans will be clinically approved. Patients will then be randomised in a 2:1 ratio to be treated according to either the functional avoidance or the standard plan. This study aims to accrue a total of 200 patients within 3 years. The primary endpoint is symptomatic radiation-induced lung toxicity, measured serially 1-12 months after RT. Secondary endpoints include: a quality of life and patient reported lung symptoms assessment, overall survival, progression-free survival, and loco-regional disease control. DISCUSSION: ASPECT trial will investigate functional avoidance method of radiation delivery in clinical practice, and will establish toxicity outcomes for patients with lung cancer undergoing curative chemo-RT. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT04676828 . Registered 1 December 2020.

Prospectively scored pulmonary toxicities in non-small cell lung cancer: Results from a randomized phase II dose escalation trial.

PURPOSE: Prospectively scored radiation pneumonitis (RP) observed in a national, randomized phase II dose-escalation trial for patients with locally advanced non-small cell lung cancer (NSCLC) was investigated. METHODS: Patients with stage IIB-IIIB histologically proven NSCLC were treated with concomitant chemo-radiotherapy (oral Vinorelbine 3times/week) at 60 Gy/30fx (A-59pts) and 66 Gy/33fx (B-58pts) from 2009 to 2013 at five Danish RT centers. Grade 2 RP (CTCAEv3.0) was investigated with univariate analysis for association with clinical and dosimetric parameters, including dyspnea and cough at baseline and during RT. Multivariable logistic regression and Cox regression with regularization were used to find a multivariable model for RP ≥ G2. RESULTS: Despite a tendency of higher mean lung dose in the high-dose arm (median[range] A = 14.9 Gy[5.8,23.1], B = 17.5 Gy[8.6,24.8], p = 0.075), pulmonary toxicities were not significantly different (RP ≥ G2 41%(A) and 52%(B), p = 0.231). A Kaplan Meier analysis of the time to RP ≥ G2 between the two arms did not reach statistical significance (p = 0.180). Statistically significant risk factors for RP ≥ G2 were GTV size (OR = 2.091/100 cm3, p = 0.002), infection at baseline or during RT (OR = 8.087, p = 0.026), dyspnea at baseline (OR = 2.184, p = 0.044) and increase of cough during RT (OR = 2.787, p = 0.008). In the multivariable logistic regression and the Cox regression analysis, the deviances of the most predictive models were within one standard deviation of the null model. CONCLUSION: No statistical difference between the high- and low dose arm was found in the risk of developing RP. The univariate analysis identified target volume, infection, dyspnea at baseline, and increase of cough during RT as risk factors for RP. The number of patients was too small to establish a statistically sound multivariable model.

The NARLAL2 dose escalation trial: dosimetric implications of inter-fractional changes in organs at risk.

BACKGROUND: Phase II trials suggested that survival rates for locally advanced lung cancer could be increased by radiotherapy dose escalation. However, results of the phase III RTOG 0617 trial illustrated an imminent risk of treatment-related death. This could be thwarted with strict constraints to organs at risk (OARs) and control of the delivered dose. This study investigates the impact of anatomical changes during radiotherapy on escalated dose distributions used in the Danish NARLAL2 dose escalation trial. MATERIAL AND METHODS: The phase III NARLAL2 trial randomizes patients between a standard and an escalated treatment plan. In the escalated arm, mean doses up to 95 Gy/33 fractions (tumour) and 74 Gy/33 fractions (lymph nodes) are delivered to the most 18fluorodeoxyglucose-positron emission tomography (18FDG PET) active regions. The dose distributions are limited by strict constraints to OARs. For a group of 27 patients, a surveillance scan (sCT) was acquired at fraction 11. The original-escalated treatment plans were recalculated on the sCTs and the impact of inter-fractional changes evaluated. RESULTS: A total of 13 patients (48%) had overdosage of least one OAR. Constraints for the oesophagus, trachea and aorta were violated in 26% of the patients. No overdosage was seen for heart or bronchi. For the connective tissue (all tissue in the mediastinum not identified as OAR or tumour) overdosage was seen in 41% of the patients and for the chest wall in 30% of the patients. The main reason for overdosage was tumour shrinkage. CONCLUSIONS: Anatomical changes during radiotherapy caused one or more OAR constraint violations for approximately half of the patient cohort. The main cause was tumour shrinkage. For lung cancer radiotherapy dose escalation trials, we recommend incorporation of adaptive radiotherapy strategies.

Systematic intrafraction shifts of mediastinal lymph node targets between setup imaging and radiation treatment delivery in lung cancer patients.

BACKGROUND AND PURPOSE: Internal target motion results in geometrical uncertainties in lung cancer radiotherapy. In this study, we determined the intrafraction motion and baseline shifts of mediastinal lymph node (LN) targets between setup imaging and treatment delivery. MATERIAL AND METHODS: Ten lung cancer patients with 2-4 fiducial markers implanted in LN targets received intensity-modulated radiotherapy with a daily setup cone-beam CT (CBCT) scan used for online soft-tissue match on the primary tumor. At a total of 122 fractions, 5 Hz fluoroscopic kV images were acquired orthogonal to the MV treatment beam during treatment delivery. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections and in the intra-treatment kV images. Baseline shifts and changes in the respiratory motion amplitude between CBCT and treatment delivery were determined from the 3D trajectories. RESULTS: Systematic mean LN baseline shifts of 2.2 mm in the cranial direction (standard deviation (SD): 1.8 mm) and 1.0 mm in the posterior direction (SD: 1.2 mm) occurred between CBCT imaging and treatment delivery. The mean motion amplitudes during CBCT and treatment delivery agreed within 0.2 mm in all directions. CONCLUSIONS: Systematic cranial and posterior intrafraction baseline shifts between CBCT and treatment delivery were observed for mediastinal LN targets. Intrafraction motion amplitudes were stable.

Difference in target definition using three different methods to include respiratory motion in radiotherapy of lung cancer.

INTRODUCTION: Minimizing the planning target volume (PTV) while ensuring sufficient target coverage during the entire respiratory cycle is essential for free-breathing radiotherapy of lung cancer. Different methods are used to incorporate the respiratory motion into the PTV. MATERIAL AND METHODS: Fifteen patients were analyzed. Respiration can be included in the target delineation process creating a respiratory GTV, denoted iGTV. Alternatively, the respiratory amplitude (A) can be measured based on the 4D-CT and A can be incorporated in the margin expansion. The GTV expanded by A yielded GTV + resp, which was compared to iGTV in terms of overlap. Three methods for PTV generation were compared. PTVdel (delineated iGTV expanded to CTV plus PTV margin), PTVσ (GTV expanded to CTV and A was included as a random uncertainty in the CTV to PTV margin) and PTV∑ (GTV expanded to CTV, succeeded by CTV linear expansion by A to CTV + resp, which was finally expanded to PTV∑). RESULTS: Deformation of tumor and lymph nodes during respiration resulted in volume changes between the respiratory phases. The overlap between iGTV and GTV + resp showed that on average 7% of iGTV was outside the GTV + resp implying that GTV + resp did not capture the tumor during the full deformable respiration cycle. A comparison of the PTV volumes showed that PTVσ was smallest and PTVΣ largest for all patients. PTVσ was in mean 14% (31 cm3) smaller than PTVdel, while PTVdel was 7% (20 cm3) smaller than PTVΣ. CONCLUSIONS: PTVσ yields the smallest volumes but does not ensure coverage of tumor during the full respiratory motion due to tumor deformation. Incorporating the respiratory motion in the delineation (PTVdel) takes into account the entire respiratory cycle including deformation, but at the cost, however, of larger treatment volumes. PTVΣ should not be used, since it incorporates the disadvantages of both PTVdel and PTVσ.

Heterogeneous FDG-guided dose-escalation for locally advanced NSCLC (the NARLAL2 trial): Design and early dosimetric results of a randomized, multi-centre phase-III study.

BACKGROUND AND PURPOSE: Local recurrence is frequent in locally advanced NSCLC and is primarily located in FDG-avid parts of tumour and lymph nodes. Aiming at improving local control without increasing toxicity, we designed a multi-centre phase-III trial delivering inhomogeneous dose-escalation driven by FDG-avid volumes, while respecting normal tissue constraints and requiring no increase in mean lung dose. Dose-escalation driven by FDG-avid volumes, delivering mean doses of 95Gy (tumour) and 74Gy (lymph nodes), was pursued and compared to standard 66Gy/33F plans. MATERIAL AND METHODS: Dose plans for the first thirty patients enroled were analysed. Standard and escalated plans were created for all patients, blinded to randomization, and compared for each patient in terms of the ability to escalate while protecting normal tissue. RESULTS: The median dose-escalation in FDG-avid areas was 93.9Gy (tumour) and 73.0Gy (lymph nodes). Escalation drove the GTV and CTV to mean doses for the tumour of 87.5Gy (GTV-T) and 81.3Gy (CTV-T) in median. No significant differences in mean dose to lung and heart between standard and escalated were found, but small volumes of e.g. the bronchi received doses between 66 and 74Gy due to escalation. CONCLUSIONS: FDG-driven inhomogeneous dose-escalation achieves large increment in tumour and lymph node dose, while delivering similar doses to normal tissue as homogenous standard plans.

A randomized phase II trial of concurrent chemoradiation with two doses of radiotherapy, 60Gy and 66Gy, concomitant with a fixed dose of oral vinorelbine in locally advanced NSCLC.

INTRODUCTION: In order to test the best performing radiation dose with a convenient chemotherapy schedule of an oral formulation of radio-sensitizing vinorelbine in inoperable locally advanced non-small cell lung cancer (NSCLC), we performed a randomized phase II trial based on a "pick the winner" design. METHODS: After 2 cycles of neoadjuvant chemotherapy, 117 patients with NSCLC stage IIB-IIIB in performance status 0-1 were randomized to radiotherapy 60Gy/30 fractions or 66Gy/33 fractions concurrent with a fixed dose of oral vinorelbine 50mg administered 3 times weekly. The primary endpoint was local progression free interval. A scheduled FDG-PET-CT-scan was performed 9months after randomization. The study was registered at ClinicalTrials.gov (NCT 00887783). RESULTS: Both arms were well tolerated. The local progression free interval at 9months was 54% in the 60Gy arm and 59% in the 66Gy arm (log rank test p=0.55). There was no statistically significant difference in overall survival. The median survival was 23.3 and 23.7months in the 60 and 66Gy arm, respectively. No significant difference in toxicity was observed. CONCLUSION: Both 60 and 66Gy administered concomitant with oral vinorelbine showed similar local control and overall survival, and was well tolerated. The pick the winner design choose 66Gy as the winning arm.

Adaptive radiotherapy for advanced lung cancer ensures target coverage and decreases lung dose.

BACKGROUND AND PURPOSE: Advanced lung cancer patients experience anatomical changes during radiotherapy. Uncorrected, these may lead to lower tumor dose, but can be corrected for by adaptive radiotherapy (ART). MATERIAL AND METHODS: Anatomical changes in 233 patients were monitored online on cone-beam CT-scans used for daily soft-tissue matching. If systematic changes above the pre-defined trigger criteria were observed, a new CT-scan, delineations, and treatment plan were made, restoring the intended dose distribution. Dose distributions with and without adaptation were compared. The first fifty ART patients were given two surveillance CT-scans during radiotherapy. These were used to evaluate delivered dose for patients without adaptation. The first fifty-two patients treated with ART were also compared with 52 pre-ART patients to evaluate the reduction in normal tissue doses. RESULTS: Sixty-three patients (27%) were adapted. Seventy-five per cent of all adaptations correctly adjusted for a decrease in tumor dose. Eighty-seven surveillance CT-scans were obtained for the first fifty patients and in only 2% of the cases, a decrease in tumor coverage (ΔV95%CTV>1%) was observed. With ART we observed a significant decrease in lung dose (MLD reduced from 14.6Gy to 12.6Gy on average). CONCLUSIONS: Implementation of soft-tissue match combined with ART decreased the lung dose. The trigger criteria used correctly identified all but one (98%) of the patients requiring adaptation with a false positive rate of 20%.

Cardiac and respiration induced motion of mediastinal lymph node targets in lung cancer patients throughout the radiotherapy treatment course.

BACKGROUND AND PURPOSE: Involved mediastinal lymph nodes (LNs) are often included in the radiotherapy target for lung cancer patients. Their motion may differ from the primary tumor motion, possibly undermining the loco-regional control. This study determines the detailed differential target motion throughout the treatment course. MATERIAL AND METHODS: Ten lung cancer patients with 2-4 fiducial markers implanted in LN targets received IMRT with a daily pre-treatment cone-beam CT (CBCT) scan. Offline, the 3D trajectory of the markers was determined from their projected trajectory in the CBCT projections. Frequency analysis was performed to separate the intrafraction motion into a respiratory and cardiac component. The mean setup error of the markers and the motion range were used to calculate margins required for LN targets when setup is based on soft-tissue match. RESULTS: Respiration motion was largest in the CC direction and more prominent for more caudal LNs. Cardiac motion was often (73%) largest in the AP direction and tended to be largest for more cranial LNs. Margins for intrafraction motion and daily baseline shifts of LNs were 4.8mm (LR), 6.0mm (CC) and 6.7mm (AP). CONCLUSIONS: Detailed mapping showed that LN motion was in general governed by breathing, but some LNs had substantial cardiac induced motion.

Acute esophagitis for patients with local-regional advanced non small cell lung cancer treated with concurrent chemoradiotherapy.

PURPOSE: Esophagitis is common in patients treated with definitive radiotherapy for local-regional advanced non small cell lung cancer (NSCLC). The purpose of this study was to estimate the dose-effect relationship using clinical and dosimetric parameters in patients receiving intensity modulated radiotherapy (IMRT) and concomitant chemotherapy (CCT). METHODS: Between 2009 and 2013, 117 patients with stages IIB-IIIB NSCLC were treated in a multicenter randomized phase II trial with 2 cycles of induction chemotherapy followed by IMRT and CCT. The esophagitis was prospectively scored using the Common Toxicity Criteria 3.0. Clinical and dosimetric variables were analyzed for the correlation with grade ⩾2 esophagitis through logistic regression. RESULTS: Grade 2 esophagitis was experienced by 31 (27%). All models including gender, institution, a dosimetric parameter and a position parameter were significantly associated with esophagitis. The two models using the relative esophagus volume irradiated above 40 Gy (V40, OR=2.18/10% volume) or the length of esophagus irradiated above 40 Gy (L40, OR=4.03/5 cm) were optimal. The upper part of esophagus was more sensitive and females experienced more toxicity than men. CONCLUSION: V40 and L40 were most effective dosimetric predictors of grade ⩾2 esophagitis. The upper part of esophagus was more sensitive.

Accuracy of 18F-FDG PET-CT in triaging lung cancer patients with suspected brain metastases for MRI.

OBJECTIVE: Brain metastases are common in lung cancer. Whole-body 2-deoxy-2-[fluorine-18]fluoro-D-glucose ([F]FDG) PET/computed tomography (CT) is used for general staging, but MRI is the best modality for characterizing brain abnormalities. We aimed to determine whether PET/CT is suitable for selecting patients for MRI on the suspicion of brain metastases. MATERIALS AND METHODS: F-FDG PET/CT (from the vertex to mid-thigh) was performed in 1108 consecutive patients suspected of lung cancer. The final diagnoses were extracted from medical records as lung cancer, with or without brain metastases, other kinds of cancers, or no cancer. The sensitivity, specificity, and positive predictive value for detecting brain metastases were calculated. Interobserver variation was tested in a subset of 88 PET/CT scans. RESULTS: Of the 1108 referred patients, 596 had lung cancer. Sixty-six had brain metastases. One PET/CT was false positive. Thirty-one scans were true positive among the 43 patients who were diagnosed with brain metastases 1 month before to 3 months after PET/CT (metastasis prevalence, 7.3%). Twelve PET/CT scans were false negative. Sensitivity, specificity, and positive predictive values were 72, 100, and 97%, respectively. Interobserver agreement between two experienced observers was high (κ=0.83), whereas agreement between the experienced and the inexperienced observer was poor. CONCLUSION: The sensitivity of brain PET/CT for detecting brain metastases in lung cancer was above 70%, and the specificity was very high. Thus, PET/CT may be suitable for selecting patients for MRI in diagnostic centers that do not perform routine MRI in the pretherapeutic staging workup. The agreement among experienced readers was very high.