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.

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.

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.

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.

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.

Clinical outcome of image-guided adaptive radiotherapy in the treatment of lung cancer patients.

BACKGROUND: Adaptive strategy with daily online tumour match is a treatment option when treating locally advanced lung cancer patients with curative intended radiotherapy (RT). MATERIAL AND METHODS: Fifty-two consecutive lung cancer patients treated with soft tissue match, adaptive RT and small planning target volumes (PTV) margins were analysed. A control group of 52 consecutive patients treated with bone match, no adaptive strategy and larger margins was included. Patients were followed with computed tomography (CT) scans every third month. CT-images showing loco-regional recurrences were identified. The recurrence gross tumour volume was delineated and registered with the original radiation treatment plan to identify site of failure. All patients were toxicity-scored using CTCAE 4.03 grading scale. Data were analysed using the Kaplan-Meier analysis. RESULTS: The median follow-up time was 16 months (3-35). Within a year, 35% of the patients in the adaptive group (ART-group) and 53% in the control group (No-ART-group) experienced loco-regional failure, showing improved loco-regional control in the ART group (p = 0.05). One patient in the ART-group and four patients in the No-ART-group showed marginal failure. Median overall progression-free survival time for the ART-group was 10 months (95% CI 8-12), and 8 months (95% CI 6-9) for the No-ART-group. Severe pneumonitis (grade 3-5) decreased from 22% in the No-ART-group to 18% in the ART-group (non-significant, p = 0.6). No significant difference in severe dysphagia was found between the two groups. CONCLUSION: In the first small cohort of patients investigated, implementation of soft-tissue tumour match and adaptive strategies for locally advanced lung cancer patients increased the loco-regional control rate without increasing treatment-related toxicity.

Evaluation of factors associated with loco-regional failure and survival in limited disease small cell lung cancer patients treated with chemoradiotherapy.

BACKGROUND: Loco-regional failure (LRF) remains a significant problem in limited disease small cell lung cancer (LD-SCLC) patients treated with definitive chemoradiotherapy. Dose-escalation may be a way forward to reduce the failure rate. However, the risk of toxicity rises with increasing doses. Knowledge on factors associated with LRF could aid the selection of patients for more aggressive treatment. Therefore, the aim of this study is to evaluate factors correlated with LRF in a cohort of LD-SCLC patients treated with definitive chemoradiotherapy. Moreover, factors associated with improved survival were investigated. MATERIAL AND METHODS: We included 147 consecutive LD-SCLC patients treated from 2007 to 2013. Radiotherapy was delivered as either 45 Gy in 1.5-Gy fractions twice daily or 46-50 Gy in 2-Gy fractions once daily. Chemotherapy was etoposide combined with either carboplatin or cisplatin given mainly concomitantly with radiotherapy. Pattern of first failure and survival were evaluated retrospectively. Cumulative LRF (CLRF) and overall survival (OS) were calculated by the Kaplan-Meier method. The impact of covariates on LRF and OS was evaluated by using Cox proportional hazards model. RESULTS: With a median follow-up time of 42.2 months, 37 patients experienced LRF as first failure. Isolated LRF was seen in 16 patients, but no isolated regional failure was seen. The CLRF rate was 22% at 1-year and 43% at 3-years. N3-stage was an independent prognostic factor correlated with LRF development (p = 0.043). Median OS was 24.1 months (95% CI 19-29 months) and a three-year survival of 34%. Prognostic factors associated with improved OS were staging including a positron emission tomography (PET) scan (p = 0.004) and receiving prophylactic cranial irradiation (PCI) (p = 0.006). CONCLUSION: N3-stage was an independent prognostic factor for LRF. Receiving a pretreatment PET scan and receiving PCI were prognostic factors for improved OS. Reduction in LRF may be achieved with dose-escalation in patients with N3-stage. This can be evaluated in prospective dose-escalation trials.

New dose constraint reduces radiation-induced fatal pneumonitis in locally advanced non-small cell lung cancer patients treated with intensity-modulated radiotherapy.

BACKGROUND: Intensity-modulated radiotherapy (IMRT) in locally advanced non-small cell lung cancer (NSCLC) allows treatment of patients with large tumour volumes, but radiation pneumonitis (RP) remains a dose limiting complication. The incidence of severe RP using three-dimensional (3D) conformal radiotherapy, was previously reported to be 17%, with 2% lethal RP. The aim of this study was to monitor the incidence of RP following the introduction of IMRT. MATERIAL AND METHODS: IMRT was delivered using 4-8 beam arrangements and introduced in three phases. In phase I, 12 patients were treated using only one dose constraint (V20), in which the total lung volume receiving 20 Gy was limited to 40%. In phase II, 25 patients were treated with an additional dose constraint of mean lung dose (MLD) ≤ 20 Gy. In phase III, 50 patients were treated with an extra dose constraint (V5) in which the total lung volume receiving a dose of 5 Gy was ≤ 60%. RP was prospectively documented. The results of phase I & II (IMRT-1) were compared to those in phase III (IMRT-2). RESULTS: The median follow-up time was 17 months. The introduction of IMRT was associated with an increase in the incidence of RP in Phase I&II (IMRT-1) to 41%, six of 37 (16%) had grade 5 RP (IMRT-1). Introducing the dose constraint V5, led to a significant reduction in the lung volume receiving doses ≤ 20 Gy from 51 ± 2% to 41 ± 1% (p < 0.0001). Introducing V5 constraint did not decrease the incidence of severe (grade ≥ 3) RP, but significantly decreased the lethal pneumonitis to 4% (two of 50 patients), p = 0.05. CONCLUSION: Introducing IMRT resulted in an increase in the incidence of severe and fatal RP, however a new dose constraint to the volume of lung receiving low doses reduced the incidence of lethal pneumonitis.

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.

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.

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.

Inter-tester reproducibility of tumour change in small cell lung cancer patients undergoing chemoradiotherapy.

BACKGROUND: Tumour volume change during delivery of chemoradiotherapy is observed in small cell lung cancer (SCLC) patients. In this study, we have compared tumour volume and anatomical changes, e.g. atelectasis or pleural effusions determined by three different methods. METHOD: A total of 37 SCLC patients undergoing thoracic radiotherapy during 2010-2011 were included. The patients were treated based on a daily three-dimensional (3D) cone beam computed tomography (CBCT) bony anatomy registration. The CBCT scans were retrospectively reviewed visually by a radiation therapist (Visual-RTT) in order to register tumour volume changes. Furthermore, the tumour volume changes were obtained by either deformable image registration (DIR) or delineation by a radiation oncologist (RO). Kappa (κ) statistics and paired t-tests were used for evaluation of the inter-tester agreement. RESULTS: The tumour volume change between the Visual-RTT, the DIR and the RO assessments obtained 84-97% agreement (κ = 0.68-0.95). Furthermore, there was no statistically significant difference between the tumour change assessment of the RO (mean 13.6 ml) and the DIR (mean 14.5 ml), p = 0.59. Tumour shrinkage was observed in 15 (41%) patients and anatomical changes in seven (19%) patients. CONCLUSION: The inter-tester reproducibility of tumour volume change between the three methods is excellent. Visual-RTT on-line inspection may be used to determine tumour shrinkage and anatomical changes as atelectasis or pleural effusions during the radiotherapy course by use of daily CBCT scans.

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.

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.

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.

A planning study of radiotherapy dose escalation of PET-active tumour volumes in non-small cell lung cancer patients.

BACKGROUND: Patients with non-small cell lung cancer (NSCLC) have poor prognosis partly because of high local failure rates. Escalating the dose to the tumour may decrease the local failure rates and thereby, improve overall survival, but the risk of complications will limit the possibility to dose-escalate a broad range of patients. Escalating only PET-active areas of the tumour may increase the potential for reaching high doses for a variety of tumour sizes and locations. MATERIAL AND METHODS: Ten patients were randomly chosen for a dose escalation planning study. A planning target volume (PTV) was defined on the mid-ventilation scan of a four-dimensional computed tomography (4D-CT) scan and a boost planning target volume (PTV-boost) was defined based on a positron emission tomography computed tomography (PET-CT) scan. Treatment plans were created aiming to reach the highest achievable of 74 Gy, 78 Gy or 82 Gy in 2 Gy per fraction prescribed to the PTV-boost without compromising normal tissue constraints and with the PTV prescribed in all cases a biological equivalent dose in 2 Gy fractions of 66 Gy. RESULTS: Nine of ten patients could be escalated to the highest dose level (82 Gy), while one patient was limited by the oesophagus dose constraint and could only reach 74 Gy. Four patients could be dose-escalated above 82 Gy without compromising normal tissue constraints. CONCLUSION: Dose-escalating only the PET-active areas of lung tumours to doses of 82 Gy while respecting normal tissue constraints is feasible, also in a series of unselected patients including cases with relatively large tumours.

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.

Daily cone-beam computed tomography used to determine tumour shrinkage and localisation in lung cancer patients.

PURPOSE/OBJECTIVE: Daily Cone-beam computed tomography (CBCT) in room imaging is used to determine tumour shrinkage during a full radiotherapy (RT) course. In addition, relative interfractional tumour and lymph node motion is determined for each RT fraction. MATERIAL AND METHODS: From November 2009 to March 2010, 20 consecutive lung cancer patients (14 NSCLC, 6 SCLC) were followed with daily CBCT during RT. The gross tumour volume for lung tumour (GTV-t) was visible in all daily CBCT scans and was delineated at the beginning, at the tenth and the 20th fraction, and at the end of treatment. Whenever visible, the gross tumour volume for lymph nodes (GTV-n) was also delineated. The GTV-t and GTV-n volumes were determined. All patients were setup according to an online bony anatomy match. Retrospectively, matching based on the internal target volume (ITV), the GTV-t or the GTV-n was performed. RESULTS: In eight patients, we observed a significant GTV-t shrinkage (15-40%) from the planning CT until the last CBCT. Only five patients presented a significant shrinkage (21-37%) in the GTV-n. Using the daily CBCT imaging, it was found that the mean value of the difference between a setup using the skin tattoo and an online matching using the ITV was 7.3±2.9 mm (3D vector in the direction of ITV). The mean difference between the ITV and bony anatomy matching was 3.0±1.3 mm. Finally, the mean distance between the GTV-t and the GTV-N was 2.9±1.6 mm. CONCLUSION: One third of all patients with lung cancer undergoing chemo-RT achieved significant tumour shrinkage from planning CT until the end of the radiotherapy. Differences in GTV-t and GTV-n motion was observed and matching using the ITV including both GTV-t and GTV-n is therefore preferable.

Matrix metalloproteinase-9 measured in urine from bladder cancer patients is an independent prognostic marker of poor survival.

INTRODUCTION: Matrix metalloproteinase 9 (MMP-9) is an endopeptidase involved in various cellular processes, such as tumour development and metastatic spread. In biological samples, MMP-9 can occur as pro-MMP-9 and active MMP-9, or these factors complexed with the inhibitor TIMP-1. An assay, which can measure active and total MMP-9 in biological samples, has been used on the urine from bladder cancer patients and demonstrated a significant correlation between MMP-9 and clinical parameters. The prognostic value of these measurements has never been investigated. Using this assay we have investigated the prognostic influence of total and active MMP-9 in urine from bladder cancer patients. MATERIAL AND METHODS: Fresh voided urines from 188 consecutive patients diagnosed with bladder cancer were collected and frozen at diagnosis. After 15 years follow-up 13 patients were still alive, and 175 patients had died. MMP-9 was measured with an immunocapture activity assay. RESULTS: Median MMP-9(total) was 173.7 units/10 g creatinine (range 0-34 792), and median MMP-9(active) was 14 units/10g creatinine (range, 0-294 757). The two factors were correlated (Spearman´s rho 0.74, p<0.0001). High MMP-9(total) and MMP-9(active) were significantly correlated with large tumour size and poor malignancy grade. Increasing tertiles of MMP-9(total) and MMP-9(active) were associated with poor overall survival (p<0.0001 and p=0.003, respectively). A Cox multivariate analysis using death as endpoint identified high tertiles of MMP-9(total) as independent prognostic markers with a relative risk 2.25 (95% confidence interval, 1.53-3.30). CONCLUSION: MMP-9 measured in urine from bladder cancer patients was a strong independent prognostic marker of poor survival. This is the first time high levels of MMP-9 measured in urine from bladder cancer patients have been linked to poor prognosis. This may reflect MMP-9 playing a role in tumour invasion and metastasis. It may be possible to non-invasively measure tumour response to therapy and identify possible tumour recurrence in an early phase.