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.

A national repository of complete radiotherapy plans: design, Results, and experiences.

BACKGROUND: Previously, many radiotherapy (RT) trials were based on a few selected dose measures. Many research questions, however, rely on access to the complete dose information. To support such access, a national RT plan database was created. The system focuses on data security, ease of use, and re-use of data. This article reports on the development and structure, and the functionality and experience of this national database. METHODS AND MATERIALS: A system based on the DICOM-RT standard, DcmCollab, was implemented with direct connections to all Danish RT centres. Data is segregated into any number of collaboration projects. User access to the system is provided through a web interface. The database has a finely defined access permission model to support legal requirements. RESULTS: Currently, data for more than 14,000 patients have been submitted to the system, and more than 50 research projects are registered. The system is used for data collection, trial quality assurance, and audit data set generation.Users reported that the process of submitting data, waiting for it to be processed, and then manually attaching it to a project was resource intensive. This was accommodated with the introduction of triggering features, eliminating much of the need for users to manage data manually. Many other features, including structure name mapping, RT plan viewer, and the Audit Tool were developed based on user input. CONCLUSION: The DcmCollab system has provided an efficient means to collect and access complete datasets for multi-centre RT research. This stands in contrast with previous methods of collecting RT data in multi-centre settings, where only singular data points were manually reported. To accommodate the evolving legal environment, DcmCollab has been defined as a 'data processor', meaning that it is a tool for other research projects to use rather than a research project in and of itself.

Bone versus soft-tissue setup in proton therapy for patients with oesophageal cancer.

BACKGROUND: The aim of this study was to investigate the effect of patient positioning based on either bone or soft-tissue matching for PT in oesophageal cancer and its impact on plan adaptation. MATERIALS AND METHODS: Two retrospective patient cohorts treated with radiotherapy were included in the study. Cohort A consisted of 26 consecutive patients with a planning 4DCT scan (CT1) and a surveillance 4DCT scan (CT2) at fraction ten. Cohort B consisted of 17 patients selected based on large anatomical changes identified during treatment resulting in a rescan (CT2). Mean dose to the iCTV (sum of the CTVs in all respiratory phases) was 50.4 Gy (RBE) in 28 fractions or 41.4 Gy (RBE) in 23 fractions. A nominal pencil beam scanning plan was created using two posterior beams and robust optimization (5 mm setup, 3.5% range). For each patient, two rigid registrations were made between average (avg) CT1 and CT2: a match on the vertebral column (bone match) and a match on the iCTV (soft-tissue match). Robustness towards setup (5 mm) and range (3.5%) errors was evaluated at CT2. Robustness towards respiration was evaluated by recalculation of the plan on all phases of the CT2 scan. Dose coverage <96% would trigger adaptation. The statistical significance (p-value <0.05) between dose coverage for the two registration methods was assessed using the Wilcoxon signed rank test. RESULTS: All plans fulfilled V95%iCTV>99% for the nominal plan and V95%iCTV>97% for all respiratory phases and robustness scenarios at CT1. In two (8%) and three (18%) patients, V95%iCTV<96% on CT2 for Cohort A and B, respectively when bone match was used. For soft-tissue match, V95%iCTV >96% for all patients. V95%iCTV was significantly higher (p-value = 0.0001) for soft-tissue match than bone match. CONCLUSION: Anatomical changes during the treatment course led to target dose deterioration and a need for plan adaptation when using a bone match.

Atlas-based auto-segmentation for delineating the heart and cardiac substructures in breast cancer radiation therapy.

BACKGROUND: This study aimed to develop and validate an automatic multi-atlas segmentation method for delineating the heart and substructures in breast cancer radiation therapy (RT). MATERIAL AND METHODS: The atlas database consisted of non-contrast-enhanced planning CT scans from 42 breast cancer patients, each with one manual delineation of the heart and 22 cardiac substructures. Half of the patients were scanned during free-breathing, the rest were scanned during a deep inspiration breath-hold. The auto-segmentation was developed in the MIM software system and validated geometrically and dosimetrically in two steps: The first validation in a small dataset to ensure consistency of the atlas. This was succeeded by a final test where multiple manual delineations in CT scans of 12 breast cancer patients were compared to the auto-segmentation. For geometric evaluation, the dice similarity coefficient (DSC) and the mean surface distance (MSD) were used. For dosimetric evaluation, the RT doses to each substructure in the manual and the automatic delineations were compared. RESULTS: In the first validation, a high geometric and dosimetric performance between the automatic and manual delineations was observed for all substructures. The final test confirmed a high agreement between the automatic and manual delineations for the heart (DSC = 0.94) and the cardiac chambers (DSC: 0.75-0.86). The difference in MSD between the automatic and manual delineations was low (<4 mm) in all structures. Finally, a high correlation between mean RT doses for the automatic and the manual delineations was observed for the heart and substructures. CONCLUSIONS: An automatic segmentation tool for delineation of the heart and substructures in breast cancer RT was developed and validated with a high correlation between the automatic and manual delineations. The atlas is pivotal for large-scale evaluations of radiation-associated heart disease.

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.

Density calibrated cone beam CT as a tool for adaptive radiotherapy.

BACKGROUND: Visual inspections of anatomical changes observed on daily cone-beam CT (CBCT) images are often used as triggers for radiotherapy plan adaptation to avoid unacceptable dose levels to the target or OARs. Direct CBCT dose calculations would improve the ability to adapt only those plans where dosimetric changes are observed. This study investigates the accuracy of dose calculations on CBCTs. MATERIALS AND METHODS: Calibration curves were obtained for CBCT imagers at nine identical accelerators. CBCT scans of a phantom with different density inserts were recorded for two scan modes (Head-Neck and Pelvis) and mean calibration curves were calculated. Subsequently, CBCT scans of the phantom with six different density inserts were recorded, the dose distributions on the CBCTs were calculated and compared to dose on the planning CT (pCT). The uncertainty was quantified by the dosimetric difference between the pCT and the CBCT. The two mean calibration curves were used to calculate the daily delivered CBCT dose for ten Head-Neck-, eleven Lung-, and ten pelvic patients. Additional patient calculations were performed using low-HU empirically corrected calibration curves. Patient doses were compared on target coverage and mean dose, and D1cc for OARs. RESULTS: The dose differences between pCT and CBCT for phantom data were small for all DVH parameters, with mean deviations below ±0.6% for both CBCT modes. For patient data, it was found that low-HU corrected calibration curves performed the best. The mean deviations for the mean dose and coverage of the target were 0.2%±0.7% and 0.1%±0.6%, across all patient groups. CONCLUSION: Dose calculation on CBCT images results in target coverage and mean dose with an accuracy of the order of 1%, which makes this acceptable for clinical use. The CBCT mode specific calibration curves can be used at all identical imaging devices and for all patient groups.

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.

Dosimetric evaluation of anatomical changes during treatment to identify criteria for adaptive radiotherapy in oesophageal cancer patients.

BACKGROUND: Some oesophageal cancer patients undergoing chemotherapy and concomitant radiotherapy (chemoRT) show large interfractional anatomical changes during treatment. These changes may modify the dose delivered to the target and organs at risk (OARs). The aim of the presenwt study was to investigate the dosimetric consequences of anatomical changes during treatment to obtain criteria for an adaptive RT decision support system. MATERIAL AND METHODS: Twenty-nine patients were treated with chemoRT for oesophageal and gastro-oesophageal junction cancer and set up according to daily cone beam computed tomography (CBCTs) scans. All patients had an additional replanning CT scan at median fraction number 10 (9-14), which was deformably registered to the original planning CT. Gross tumour volumes (GTVs), clinical target volumes (CTVs) and OARs were transferred to the additional CT and corrected by an exwperienced physician. Treatment plans were recalculated and dose to targets and OARs was evaluated. Treatment was adapted if the volume receiving 95% of the prescribed dose (V95%) coverage of CTV decreased > 1% or planning target volume (PTV) decreased by > 3%. RESULTS: In total, nine adaptive events were observed: All nine were triggered by PTV V95% decrease > 3% [median 11% (5-41%)] and six of these were additionally triggered by CTV V95% decrease > 1% [median 5% (2-35%)]. The largest discrepancies were caused by interfractional baseline or amplitude shifts in diaphragm position (n = 5). Mediastinal (n = 6), oesophageal (n = 6) and bowel filling changes (n = 2) caused the remainder of the changes. For patients with dosimetric changes exceeding the adaptation limits, the discrepancies were confirmed by inspecting the daily CBCTs. In 31% of all patients, heart V30Gy increased more than 2% (maximum 5%). Only minor changes in lung dose or liver dose were seen. CONCLUSION: Target coverage throughout the course of chemoRT treatment is compromised in some patients due to interfractional anatomical changes. Dose to the heart may increase as well.

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.

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.

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.

Is integrated transit planar portal dosimetry able to detect geometric changes in lung cancer patients treated with volumetric modulated arc therapy?

BACKGROUND: Geometric changes are frequent during the course of treatment of lung cancer patients. This may potentially result in deviations between the planned and actual delivered dose. Electronic portal imaging device (EPID)-based integrated transit planar portal dosimetry (ITPD) is a fast method for absolute in-treatment dose verification. The aim of this study was to investigate if ITPD could detect geometric changes in lung cancer patients. MATERIALS AND METHODS: A total of 460 patients treated with volumetric modulated arc therapy (VMAT) following daily cone beam computed tomography (CT)-based setup were visually inspected for geometrical changes on a daily basis. Forty-six patients were subject to changes and had a re-CT and an adaptive treatment plan. The reasons for adaptation were: change in atelectasis (n = 18), tumor regression (n = 9), change in pleural effusion (n = 8) or other causes (n = 11). The ITPDs were calculated on both the initial planning CT and the re-CT and compared with a global gamma (γ) evaluation (criteria: 3%\3mm). A treatment fraction failed when the percentage of pixels failing in the radiation fields exceeded 10%. Dose-volume histograms (DVHs) were compared between the initial plan versus the plan re-calculated on the re-CT. RESULTS: The ITPD threshold method detected 76% of the changes in atelectasis, while only 50% of the tumor regression cases and 42% of the pleural effusion cases were detected. Only 10% of the cases adapted for other reasons were detected with ITPD. The method has a 17% false-positive rate. No significant correlations were found between changes in DVH metrics and γ fail-rates. CONCLUSIONS: This study showed that most cases with geometric changes caused by atelectasis could be captured by ITPD, however for other causes ITPD is not sensitive enough to detect the clinically relevant changes and no predictive power of ITPD was found.

Clinical use of iterative 4D-cone beam computed tomography reconstructions to investigate respiratory tumor motion in lung cancer patients.

BACKGROUND: Cone beam computed tomography (CBCT) provides means for respiratory resolved volumetric imaging of the thorax. However, merely sorting the acquired projections into respiratory phases and performing a series of conventional three-dimensional (3D) reconstructions lead to clinically prohibitive reconstruction artifacts. This problem can be mitigated by iterative 4D reconstruction. We present a clinical evaluation of two iterative 4D-CBCT reconstruction algorithms during stereotactic body radiation therapy. MATERIAL AND METHODS: Two types of iterative 4D-CBCT reconstructions were performed utilizing: 1) total variation (TV) minimization; and 2) optical flow (OF) based deformable registration between phases. The reconstructions were initially evaluated on a lung phantom with a moveable target insert. Subsequently, 4D-CBCT reconstructions were performed for 19 patients on 2-3 CBCT projection datasets previously acquired for conventional 3D-CBCT reconstruction (∼650 half-fan projections per scan in a full one-minute gantry rotation). The 4D reconstructions were imported into a treatment planning system, where the gross tumor volume (GTV) was delineated and used to extract the tumor motion amplitude. RESULTS: For both phantom and patient scans, the iterative 4D-CBCT reconstructions had sufficient quality for GTV delineation when the breathing period was faster than 3.5 seconds (15 of 19 patients), but not for slower breathing periods (4 patients). The 3D tumor motion amplitude for the patients was significantly lower (p = 10(-6), Wilcoxon signed rank test) in the OF reconstructions (mean 4.0 mm) than in the TV reconstructions (mean 5.3 mm). CONCLUSION: TV and OF iterative 4D-CBCT reconstruction of the thorax in a lung phantom and for 19 patients was demonstrated from standard CBCT scans and used to estimate the daily lung tumor motion.

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.

Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

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.

Dosimetric impact of respiratory motion, interfraction baseline shifts, and anatomical changes in radiotherapy of non-small cell lung cancer.

BACKGROUND: The survival rates for patients with non-small cell lung cancer (NSCLC) may be improved by dose escalation; however, margin reduction may be required in order to keep the toxicity at an acceptable level. In this study we have investigated the dosimetric impact of tumor motion and anatomical changes during intensity-modulated radiotherapy (IMRT) of patients with NSCLC. MATERIAL AND METHODS: Sixteen NSCLC patients received IMRT with concomitant chemotherapy. The tumor and lymph node targets were delineated in the mid-ventilation phase of a planning 4DCT scan (CT1). Typically 66 Gy was delivered in 33 fractions using daily CBCT with bony anatomy match for patient setup. The daily baseline shifts of the mean tumor position relative to the spine were extracted from the CBCT scans. A second 4DCT scan (CT2) was acquired halfway through the treatment course and the respiratory tumor motion was extracted. The plan was recalculated on CT2 with and without inclusion of the respiratory tumor motion and baseline shifts in order to investigate the impact of tumor motion and anatomical changes on the tumor dose. RESULTS: Respiratory tumor motion was largest in the cranio-caudal (CC) direction (range 0-13.1 mm). Tumor baseline shifts up to 18 mm (CC direction) and 24 mm (left-right and anterior-posterior) were observed. The average absolute difference in CTV mean dose to the primary tumor (CTV-t) between CT1 and CT2 was 1.28% (range 0.1-4.0%) without motion. Respiratory motion and baseline shifts lead to average absolute CTV-t mean dose changes of 0.46% (0-1.9%) and 0.65% (0.0-2.1%), respectively. For most patients, the changes in the CTV-t dose were caused by anatomical changes rather than internal target motion. CONCLUSION: Anatomical changes had larger impact on the target dose distribution than internal target motion. Adaptive radiotherapy could be used to achieve better target coverage throughout the treatment course.

Repeated deep-inspiration breath-hold CT scans at planning underestimate the actual motion between breath-holds at treatment for lung cancer and lymphoma patients.

PURPOSE/OBJECTIVE: Deep-inspiration breath-hold (DIBH) during radiotherapy may reduce dose to the lungs and heart compared to treatment in free breathing. However, intra-fractional target shifts between several breath-holds may decrease target coverage. We compared target shifts between four DIBHs at the planning-CT session with those measured on CBCT-scans obtained pre- and post-DIBH treatments. MATERIAL/METHODS: Twenty-nine lung cancer and nine lymphoma patients were treated in DIBH. An external gating block was used as surrogate for the DIBH-level with a window of 2 mm. Four DIBH CT-scans were acquired: one for planning (CTDIBH3) and three additional (CTDIBH1,2,4) to assess the intra-DIBH target shifts at scanning by registration to CTDIBH3. During treatment, pre-treatment (CBCTpre) and post-treatment (CBCTpost) scans were acquired. For each pair of CBCTpre/post, the target intra-DIBH shift was determined. For lung cancer, tumour (GTV-Tlung) and lymph nodes (GTV-Nlung) were analysed separately. Group mean (GM), systematic and random errors, and GM for the absolute maximum shifts (GMmax) were calculated for the shifts between CTDIBH1,2,3,4 and between CBCTpre/post. RESULTS: For GTV-Tlung, GMmax was larger at CBCT than CT in all directions. GMmax in cranio-caudal direction was 3.3 mm (CT)and 6.1 mm (CBCT). The standard deviations of the shifts in the left-right and cranio-caudal directions were larger at CBCT than CT. For GTV-Nlung and CTVlymphoma, no difference was found in GMmax or SD. CONCLUSION: Intra-DIBH shifts at planning-CT session are generally smaller than intra-DIBH shifts observed at CBCTpre/post and therefore underestimate the intra-fractional DIBH uncertainty during treatment. Lung tumours show larger intra-fractional variations than lymph nodes and lymphoma targets.