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.

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.

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.

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.

Proposal for the delineation of neoadjuvant target volumes in oesophageal cancer.

PURPOSE: To define instructions for delineation of target volumes in the neoadjuvant setting in oesophageal cancer. MATERIALS AND METHODS: Radiation oncologists of five European centres participated in the following consensus process: [1] revision of published (MEDLINE) and national/institutional delineation guidelines; [2] first delineation round of five cases (patient 1-5) according to national/institutional guidelines; [3] consensus meeting to discuss the results of step 1 and 2, followed by a target volume delineation proposal; [4] circulation of proposed instructions for target volume delineation and atlas for feedback; [5] second delineation round of five new cases (patient 6-10) to peer review and validate (two additional centres) the agreed delineation guidelines and atlas; [6] final consensus on the delineation guidelines depicted in an atlas. Target volumes of the delineation rounds were compared between centres by Dice similarity coefficient (DSC) and maximum/mean undirected Hausdorff distances (Hmax/Hmean). RESULTS: In the first delineation round, the consistency between centres was moderate (CTVtotal: DSC = 0.59-0.88; Hmean = 0.2-0.4 cm). Delineations in the second round were much more consistent. Lowest variability was obtained between centres participating in the consensus meeting (CTVtotal: DSC: p < 0.050 between rounds for patients 6/7/8/10; Hmean: p < 0.050 for patients 7/8/10), compared to validation centres (CTVtotal: DSC: p < 0.050 between validation and consensus meeting centres for patients 6/7/8; Hmean: p < 0.050 for patients 7/10). A proposal for delineation of target volumes and an atlas were generated. CONCLUSION: We proposed instructions for target volume delineation and an atlas for the neoadjuvant radiation treatment in oesophageal cancer. These will enable a more uniform delineation of patients in clinical practice and clinical trials.

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.

Time and dose-related changes in lung perfusion after definitive radiotherapy for NSCLC.

BACKGROUND AND PURPOSE: To examine radiation-induced changes in regional lung perfusion per dose level in 58 non-small-cell lung cancer (NSCLC) patients treated with intensity-modulated radiotherapy (IMRT). MATERIAL AND METHODS: NSCLC patients receiving chemo-radiotherapy (RT) of minimum 60 Gy were included prospectively in the study. Lung perfusion single-photon emission computed tomography (SPECT/CT) was performed before and serially after RT. Changes (relative to baseline, %) in regional lung perfusion were correlated with regional dose. Toxicity outcome was radiation pneumonitis (RP) CTC grades 2-5. RESULTS: Perfusion changes were associated with dose. Dose-dependent reduction in regional perfusion was observed at 3, 6 and 12 months of follow-up. Relative perfusion loss per dose bin was 4% at 1 month, 14% at 3 months, 13% at 6 months and 21% at 12 months after RT. In patients with RP, perfusion reduction was larger in high dose lung regions, compared to those without RP. Low dose regions, on the contrary, revealed perfusion gain in the patients with RP. CONCLUSION: Progressive dose dependent perfusion loss is manifested on SPECT up to 12 months following IMRT. These findings suggest that the dynamic change in perfusion may have prognostic value in predicting radiation pneumonitis in NSCLC patients treated with IMRT.

Inclusion of functional information from perfusion SPECT improves predictive value of dose-volume parameters in lung toxicity outcome after radiotherapy for non-small cell lung cancer: A prospective study.

BACKGROUND AND PURPOSE: To compare functional and standard dose-volume parameters as predictors of postradiation pulmonary toxicity in lung cancer patients undergoing curative chemo-radiotherapy (RT) studied prospectively. MATERIAL AND METHODS: A total of 58 patients treated with Intensity Modulated RT (60-66Gy) were analysed. Standard dose-volume parameters were extracted from treatment planning computed tomography (CT) scans. Corresponding functional dose-volume parameters were calculated from perfusion single-photon emission computed tomography (SPECT). Primary end-point was radiation pneumonitis (RP) grade 2-5. RESULTS: Functional mean lung dose (MLD) and lung volumes receiving 5, 10, 20 and 30Gy (V5-V30, respectively) revealed high correlation with corresponding standard parameters (r>0.8). Standard MLD, V20 and V30 were significantly higher in patients with RP (p=0.01). All functional parameters were significantly higher in the RP patients (p<0.03). In multivariate analysis functional parameters produced superior risk estimates, while all standard parameters, except V30, were not related to the risk of RP. Area under the curve (AUC) for functional metrics generally exceeded the AUC for corresponding standard parameters, but they were not significantly different from each other. CONCLUSION: SPECT-based functional parameters were better to predict the risk of RP compared to standard CT-based dose-volume parameters. Functional parameters may be useful to guide radiotherapy planning in order to reduce the risk of radiation-induced toxicity.

Loss of lung function after chemo-radiotherapy for NSCLC measured by perfusion SPECT/CT: Correlation with radiation dose and clinical morbidity.

BACKGROUND: The purpose of the study was to assess dose and time dependence of radiotherapy (RT)-induced changes in regional lung function measured with single photon emission computed tomography (SPECT) of the lung and relate these changes to the symptomatic endpoint of radiation pneumonitis (RP) in patients treated for non-small cell lung cancer (NSCLC). MATERIAL AND METHODS: NSCLC patients scheduled to receive curative RT of minimum 60 Gy were included prospectively in the study. Lung perfusion SPECT/CT was performed before and three months after RT. Reconstructed SPECT/CT data were registered to treatment planning CT. Dose to the lung was segmented into regions corresponding to 0-5, 6-20, 21-40, 41-60 and > 60 Gy. Changes (%) in regional lung perfusion before and after RT were correlated with regional dose and symptomatic RP (CTC grade 2-5) outcome. RESULTS: A total of 58 patients were included, of which 45 had three-month follow-up SPECT/CT scans. Analysis showed a statistically significant dose-dependent reduction in regional perfusion at three-month follow-up. The largest population composite perfusion loss was in 41-60 Gy (42.2%) and > 60 Gy (41.7%) dose bins. Lung regions receiving low dose of 0-5 Gy and 6-20 Gy had corresponding perfusion increase (-7.2% and -6.1%, respectively). Regional perfusion reduction was different in patients with and without RP with the largest difference in 21-40 Gy bin (p = 0.02), while for other bins the difference did not reach statistical significance. The risk of symptomatic RP was higher for the patients with perfusion reduction after RT (p = 0.02), with the relative risk estimate of 3.6 (95% CI 1.1-12). CONCLUSION: Perfusion lung function changes in a dose-dependent manner after RT. The severity of radiation-induced lung symptoms is significantly correlated with SPECT perfusion changes. Perfusion reduction early after RT is associated with a high risk of later development of symptomatic RP.

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.

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.

Development of radiation pneumopathy and generalised radiological changes after radiotherapy are independent negative prognostic factors for survival in non-small cell lung cancer patients.

BACKGROUND AND PURPOSE: To investigate the risk factors for radiation pneumopathy (RP) and survival rate of non-small cell lung cancer patients with RP and generalised interstitial lung changes (gen-ILC). MATERIAL AND METHODS: A total of 147 consecutive patients receiving curative radiotherapy were analysed. RP was graded according to Common Terminology Criteria for Adverse Events v. 3. Computed tomography images were assessed for the presence of gen-ILC after radiotherapy. Univariate and multivariate analyses were performed to identify significant factors. RESULTS: Median follow-up was 16.2 months (range 1.4-58.6). Radiological changes after radiotherapy were confined to high dose irradiation volume in 111 patients, while 31 patients developed gen-ILC. Dosimetric parameters and level of C-reactive protein before radiotherapy were significantly associated with severe RP. Development of gen-ILC (p=0.008), as well as severe RP (p=0.03) had significant negative impact on patients' survival. These two factors remained significant in the multivariate analysis. CONCLUSIONS: Severe radiation pneumopathy and generalised radiographic changes were significant independent prognostic factors for survival. More studies on pathophysiology of radiation induced damage are necessary to fully understand the mechanisms behind it.