Iris Ernst

Safety and Efficacy of Stereotactic Body Radiotherapy for Stage I Non-Small-Cell Lung Cancer in Routine Clinical Practice A Patterns-of-Care and Outcome Analysis

Introduction: To evaluate safety and efficacy of stereotactic body radiotherapy (SBRT) for stage I non–small-cell lung cancer (NSCLC) in a patterns-of-care and patterns-of-outcome analysis. Methods: The working group “Extracranial Stereotactic Radiotherapy” of the German Society for Radiation Oncology performed a retrospective multicenter analysis of practice and outcome after SBRT for stage I NSCLC. Sixteen German and Austrian centers with experience in pulmonary SBRT were asked to participate. Results: Data of 582 patients treated at 13 institutions between 1998 and 2011 were collected; all institutions, except one, were academic hospitals. A time trend to more advanced radiotherapy technologies and escalated irradiation doses was observed, but patient characteristics (age, performance status, pulmonary function) remained stable over time. Interinstitutional variability was substantial in all treatment characteristics but not in patient characteristics. After an average follow-up of 21 months, 3-year freedom from local progression (FFLP) and overall survival (OS) were 79.6% and 47.1%, respectively. The biological effective dose was the most significant factor influencing FFLP and OS: after more than 106 Gy biological effective dose as planning target volume encompassing dose (N = 164), 3-year FFLP and OS were 92.5% and 62.2%, respectively. No evidence of a learning curve or improvement of results with larger SBRT experience and implementation of new radiotherapy technologies was observed. Conclusion: SBRT for stage I NSCLC was safe and effective in this multi-institutional, academic environment, despite considerable interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influencing local tumor control and OS.

Detection of respiratory tumour motion using intrinsic list mode-driven gating in positron emission tomography

PurposeRespiratory motion of organs during PET scans is known to degrade PET image quality, potentially resulting in blurred images, attenuation artefacts and erroneous tracer quantification. List mode-based gating has been shown to reduce these pitfalls in cardiac PET. This study evaluates these intrinsic gating methods for tumour PET scans.MethodsA total of 34 patients with liver or lung tumours (14 liver tumours and 27 lung tumours in all) underwent a 15-min single-bed list mode PET scan of the tumour region. Of these, 15 patients (8 liver and 11 lung tumours in total) were monitored by a video camera registering a marker on the patient’s abdomen, thus capturing the respiratory motion for PET gating (video method). Further gating information was deduced by dividing the list mode stream into 200-ms frames, determining the number of coincidences (sensitivity method) and computing the axial centre of mass of the measured count rates in the same frames (centre of mass method). Additionally, these list mode-based methods were evaluated using only coincidences originating from the tumour region by segmenting the tumour in sinogram space (segmented sensitivity/centre of mass method). Measured displacement of the tumours between end-expiration and end-inspiration and the increase in apparent uptake in the gated images served as a measure for the exactness of gating. To estimate the accuracy, a thorax phantom study with moved activity sources simulating small tumours was also performed.ResultsAll methods resolved the respiratory motion with varying success. The best results were seen in the segmented centre of mass method, on average leading to larger displacements and uptake values than the other methods. The simple centre of mass method performed worse in terms of displacements due to activities moving into the field of view during the respiratory cycle. Both sensitivity- and video-based methods lead to similar results.ConclusionList mode-driven PET gating, especially the segmented centre of mass method, is feasible and accurate in PET scans of liver and lung tumours.

Applicability of the linear-quadratic formalism for modeling local tumor control probability in high dose per fraction stereotactic body radiotherapy for early stage non-small cell lung cancer.

BACKGROUND AND PURPOSE To compare the linear-quadratic (LQ) and the LQ-L formalism (linear cell survival curve beyond a threshold dose dT) for modeling local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC). MATERIALS AND METHODS This study is based on 395 patients from 13 German and Austrian centers treated with SBRT for stage I NSCLC. The median number of SBRT fractions was 3 (range 1-8) and median single fraction dose was 12.5 Gy (2.9-33 Gy); dose was prescribed to the median 65% PTV encompassing isodose (60-100%). Assuming an α/β-value of 10 Gy, we modeled TCP as a sigmoid-shaped function of the biologically effective dose (BED). Models were compared using maximum likelihood ratio tests as well as Bayes factors (BFs). RESULTS There was strong evidence for a dose-response relationship in the total patient cohort (BFs>20), which was lacking in single-fraction SBRT (BFs<3). Using the PTV encompassing dose or maximum (isocentric) dose, our data indicated a LQ-L transition dose (dT) at 11 Gy (68% CI 8-14 Gy) or 22 Gy (14-42 Gy), respectively. However, the fit of the LQ-L models was not significantly better than a fit without the dT parameter (p=0.07, BF=2.1 and p=0.86, BF=0.8, respectively). Generally, isocentric doses resulted in much better dose-response relationships than PTV encompassing doses (BFs>20). CONCLUSION Our data suggest accurate modeling of local tumor control in fractionated SBRT for stage I NSCLC with the traditional LQ formalism.

Late effects of thoracic irradiation in children.

Purpose:To summarize the literature regarding the late effects of radiotherapy to the thorax in childhood and adolescence with special emphasis on cardiac and pulmonary impairment.Material and Methods:The literature was critically reviewed using the PubMed® database with the key words “late effects”, “late sequelae”, “child”, “childhood”, “adolescence”, “radiation”, “radiotherapy”, “thorax”, “lung”, “heart”, and “pulmonary”.Results:17 publications dealing with radiation-induced pulmonary and cardiac late sequelae in children could be identified and were analyzed in detail. 29 further publications with additional information were also included in the analysis. Pulmonary function impairment after mediastinal irradiation arose in one third of all pediatric patients, even when treatment was performed with normofractionated lower doses (15–25 Gy). Whole lung irradiation was regularly followed by pulmonary function impairment with differing rates in several reports. However, clinically symptomatic function impairment like dyspnea was less frequent. Irradiation of up to 25 Gy (single doses ≤ 2 Gy) to the heart showed little or no cardiac toxicity in analyses of irradiated children (median follow-up 1.3–14.3 years). Doses of > 25 Gy (single doses ≤ 2–3.3 Gy) led to several cardiac dysfunctions. However, new data from adults with longer follow-up may indicate threshold doses as low as 1 Gy. Impairment of skeletal growth, breast hypoplasia, and secondary malignancy were further potential late sequelae.Conclusion:Several retrospective reports described radiation-associated late sequelae in children. However, there is still a lack of sufficient data regarding the characterization of dose-volume effects.Ziel:Zusammenfassung der Literatur bezüglich Spätfolgen nach Strahlentherapie am Thorax bei Kindern und Jugendlichen mit einem Schwerpunkt auf kardialen und pulmonalen Funktionseinschränkungen.Material und Methodik:Literaturzusammenstellung mittels der PubMed®-Datenbank mit den Suchbegriffen „late effects“, „late sequelae“, „child“, „childhood“, „adolescence“, „radiation“, „radiotherapy“, „thorax“, „lung“, „heart“ und „pulmonary“.Ergebnisse:17 Publikationen mit Daten zu strahlentherapieinduzierten pulmonalen und kardialen Spätfolgen bei Kindern wurden identifiziert und detailliert analysiert. Weitere 29 Publikationen mit zusätzlichen Informationen wurden in die Analyse mit eingeschlossen. Pulmonale Funktionseinschränkungen nach mediastinaler Bestrahlung im Kindesalter traten bei einem Drittel aller Patienten auf, auch wenn die Behandlung normofraktioniert mit Dosen von 15–25 Gy durchgeführt wurde (Tabelle 1a). Eine Ganzlungenbestrahlung ging regelmäßig mit einer gewissen Einschränkung einher (Tabelle 1b). Symptomatische Funktionseinschränkungen wie Dyspnoe waren jedoch seltener. Eine Bestrahlung bis zu 25 Gy am Herzen (Einzeldosen ≤ 2 Gy) zeigte keine oder wenige kardiale Spätfolgen in den Analysen zur Bestrahlung im Kindesalter (mediane Nachbeobachtung 1,3–14,3 Jahre). Höhere Bestrahlungsdosen > 25 Gy (Einzeldosen ≤ 2–3,3 Gy) führten zu einigen kardialen Spätfolgen (Tabelle 2). Allerdings deuten neue Daten bei Erwachsenen auf Dosisschwellenwerte von 1 Gy hin. Wachstumsstörungen, Brusthypoplasien und Sekundärmalignome wurden ebenso beschrieben.Schlussfolgerung:Einige retrospektive Berichte beschreiben strahlentherapieassoziierte Spätfolgen im Kindesalter. Allerdings gibt es keine suffizienten Daten bezüglich der Charakterisierung von Dosis-Volumen-Effekten.

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy

BACKGROUND AND PURPOSE To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. MATERIALS AND METHODS A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. RESULTS After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. CONCLUSIONS Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases.

Organ movements and dose exposures in teletherapy of prostate cancer using a rectal balloon.

Background and Purpose:During radiotherapy of localized prostate cancer, organ movements for the dose exposure of organs at risk like rectum, urinary bladder and urethra play, inter alia, a significant role. One possibility of internal organ stabilizing is offered by the usage of a rectal balloon during radiotherapy. The influence on organ movements and dose allocation of the organs at risk is unknown.Patients and Methods:Twelve patients (Table 1) were characterized based on planning-CTs regarding organ movements and organ doses using a rectal balloon, inflated with 0 ml and 60 ml air. For the determination of the organ doses, three-dimensional conformal radiation plans (3-field-pelvis box) with a cumulative dose of 59.4 Gy were created, and the dose-volume-histograms for the anterior rectal wall, the posterior rectal wall, the rectal mucosa, the whole rectum, as well as the urinary bladder were compared (Figures 1 and 2).Results:The application of a 60 ml air-filled rectal balloon during each fraction of teletherapy led to significant organ movements of the anterior and posterior rectal wall and to a reduction of the transversal prostate diameter, as well as to a changed organ dose exposure of the organs at risk. A ventral shift of the anterior rectal wall (maximum 0.8 cm, mean 0.4 cm) was shown, as well as a dorsal shift of the posterior rectal wall (maximum 1.2 cm, mean 0.7 cm), associated with a transversal prostate diameter decrease (maximum 0.8 cm, mean 0.3 cm) (Table 2, Figure 3). The organ dose of the anterior rectal wall increased significantly (maximum 1.3 Gy, mean 0.5 Gy) during application of a rectal balloon, the one of the posterior rectal wall decreased significantly (maximum 18.6 Gy, mean 6.5 Gy). Related to the entire rectal mucosa and the rectum as a complete organ, a decrease of the maximum doses was shown (rectal mucosa: maximum 9.1 Gy, mean 3.0 Gy; rectum: maximum 9.4 Gy, mean 3.7 Gy). The organ dose of the urinary bladder did not show significant changes (Tables 3 and 4, Figures 4 to 7).Conclusion:The application of a rectal balloon in teletherapy of localized prostate cancer leads to significantly changed dose exposition of organs at risk. The decreased dose exposure of the posterior rectal wall and the rectal mucosa is opposed by the higher organ dose of the anterior rectal wall. It has to be shown weather documented organ dose exposure is associated with short and long-term consequences.Hintergrund und Ziel:Bei der Strahlentherapie des lokalisierten Prostatakarzinoms spielen unter anderem die Organbewegungen für die Dosisexposition der Risikoorgane Rektum, Harnblase und Harnröhre eine entscheidende Rolle. Eine Möglichkeit der internen Organstabilisierung stellt die Verwendung eines Rektumballons bei der Strahlentherapie dar. Der Einfluss auf die Organbewegungen und die Dosisverteilung an den jeweiligen Risikoorganen ist unklar.Patienten und Methodik:12 Patienten (Tabelle 1) wurden auf der Grundlage von Planungs-Computertomogrammen hinsichtlich Organbewegungen und Organdosen unter Verwendung eines Rektumballons mit 0 ml und 60 ml Luftfüllung charakterisiert. Für die Bestimmung der Organdosen wurden dreidimensionale konformale Bestrahlungspläne (3-Felder-Beckenbox) mit einer Gesamtdosis von 59,4 Gy erstellt und die Dosis-Volumen-Histogramme für die Rektumvorderwand, die Rektumhinterwand, die Rektumschleimhaut, das gesamte Rektum sowie die Harnblase verglichen (Abbildungen 1 und 2).Ergebnisse:Die Verwendung eines mit 60 ml Luft gefüllten Rektumballons bei der Teletherapie führte zu signifikanten Organbewegungen im Bereich der Rektumvorderwand, Rektumhinterwand und zu einer Reduzierung des transversalen Prostatadurchmessers sowie zu veränderten Organdosen der Risikoorgane. Es zeigte sich eine Ventralverschiebung der Rektumvorderwand (Maximum 0,8 cm, Mittel 0,4 cm) sowie eine Dorsalverschiebung der Rektumhinterwand (Maximum 1,2 cm, Mittel 0,7 cm), verbunden mit einer Reduktion des transversalen Prostatadurchmessers (Maximum 0,8 cm, Mittel 0,3 cm) (Tabelle 2, Abbildung 3). Die Organdosis der Rektumvorderwand nahm unter Verwendung eines Rektumballons signifikant zu (Maximum 1,3 Gy, Mittel 0,5 Gy), die der Rektumhinterwand signifikant ab (Maximum 18,6 Gy, Mittel 6,5 Gy). Bezogen auf die gesamte Rektumschleimhaut und das Rektum als Gesamtorgan zeigte sich eine Reduktion der Maximaldosen (Rektumschleimhaut: max. 9,1 Gy, Mittel 3,0 Gy, Rektum: maximal 9,4 Gy, Mittel 3,7 Gy). Die Organdosis der Harnblase zeigte keine signifikante Veränderung (Tabellen 3 und 4, Abbildungen 4–7).Schlussfolgerung:Die Verwendung eines Rektumballons bei der Teletherapie des lokalisierten Prostatakarzinoms führt zu signifikant veränderter Dosisexposition von Risikoorganen. Geringeren Organdosen an Rektumhinterwand und Rektumschleimhaut steht eine höhere Organdosis der Rektumvorderwand entgegen. Inwieweit die unterschiedlichen Organdosen einen Einfluss auf Akut- und Spätfolgen haben, muss Gegenstand weiterer Untersuchungen sein.

Stereotactic body radiotherapy for liver tumors: principles and practical guidelines of the DEGRO Working Group on Stereotactic Radiotherapy.

PurposeThis report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a practical guideline for safe and effective stereotactic body radiotherapy (SBRT) of liver tumors.MethodsThe literature on the clinical evidence of SBRT for both primary liver tumors and liver metastases was reviewed and analyzed focusing on both physical requirements and special biological characteristics.ResultsRecommendations were developed for patient selection, imaging, planning, treatment delivery, motion management, dose reporting, and follow-up. Radiation dose constraints to critical organs at risk are provided.ConclusionSBRT is a well-established treatment option for primary and secondary liver tumors associated with low morbidity.ZusammenfassungZielDie Arbeitsgruppe Stereotaxie der Deutschen Gesellschaft für Radioonkologie (DEGRO) legt hier eine Empfehlung zur sicheren und effektiven Durchführung der SBRT von Lebertumoren vor.MethodenEine Literaturrecherche zur Untersuchung der Evidenz der SBRT sowohl für primäre Lebertumore als auch für Lebermetastasen wurde durchgeführt. Auf dieser Basis werden Empfehlungen für technisch-physikalische Voraussetzungen wie auch für die tägliche Praxis der Leber-SBRT gegeben. Weiterhin werden radiobiologische Besonderheiten dieses Verfahrens dargestellt.ErgebnissePraktische Vorgaben werden für Patientenselektion, Bildgebung, Planung, Applikation, Bewegungsmanagement, Dosisdokumentation und Follow-up gegeben. Dosisempfehlungen für die kritischen Risikoorgane werden dargestellt.SchlussfolgerungDie SBRT stellt eine etablierte Behandlungsmethode für primäre und sekundäre Lebertumore dar und ist mit niedriger Morbidität assoziiert.

Stereotactic body radiotherapy (SBRT) for medically inoperable lung metastases—A pooled analysis of the German working group “stereotactic radiotherapy”

OBJECTIVES The current literature on stereotactic body radiotherapy (SBRT) for oligometastatic disease is characterized by small patient cohorts with heterogeneous primary tumors, metastases location and dose regimes. Hence, this study established a multi-institutional database of 700 patients treated with SBRT for pulmonary metastases to identify prognostic factors influencing survival and local control. MATERIALS AND METHODS All German radiotherapy departments were contacted and invited to participate in this analysis. A total number of 700 patients with medically inoperable lung metastases treated with SBRT in 20 centers between 1997 and 2014 were included in a database. Primary and metastatic tumor characteristics, treatment characteristics and follow-up data including survival, local control, distant metastases, and toxicity were evaluated. Lung metastases were treated with median PTV-encompassing single doses of 12.5Gy (range 3.0-33.0Gy) in a median number of 3 fractions (range 1-13). RESULTS After a median follow-up time of 14.3 months, 2-year local control (LC) and overall survival (OS) were 81.2% and 54.4%, respectively. In multivariate analysis, OS was most significantly influenced by pretreatment performance status, maximum metastasis diameter, primary tumor histology, time interval between primary tumor diagnosis and SBRT treatment and number of metastases. For LC, independent prognostic factors were pretreatment performance status, biological effective dose (BED) at PTV isocenter (BEDISO) and single fraction (PTV-encompassing) dose in multivariate analysis. Radiation-induced pneumonitis grade 2 or higher was observed in 6.5% of patients. The only factor significantly influencing toxicity was BEDISO (p=0.006). CONCLUSION SBRT for medically inoperable patients with pulmonary metastases achieved excellent local control and promising overall survival. Important prognostic factors were identified for selecting patients who might benefit most from this therapy approach.

Stereotactic body radiotherapy for liver tumors

PurposeThis report of the Working Group on Stereotactic Radiotherapy of the German Society of Radiation Oncology (DEGRO) aims to provide a practical guideline for safe and effective stereotactic body radiotherapy (SBRT) of liver tumors.MethodsThe literature on the clinical evidence of SBRT for both primary liver tumors and liver metastases was reviewed and analyzed focusing on both physical requirements and special biological characteristics.ResultsRecommendations were developed for patient selection, imaging, planning, treatment delivery, motion management, dose reporting, and follow-up. Radiation dose constraints to critical organs at risk are provided.ConclusionSBRT is a well-established treatment option for primary and secondary liver tumors associated with low morbidity.ZusammenfassungZielDie Arbeitsgruppe Stereotaxie der Deutschen Gesellschaft für Radioonkologie (DEGRO) legt hier eine Empfehlung zur sicheren und effektiven Durchführung der SBRT von Lebertumoren vor.MethodenEine Literaturrecherche zur Untersuchung der Evidenz der SBRT sowohl für primäre Lebertumore als auch für Lebermetastasen wurde durchgeführt. Auf dieser Basis werden Empfehlungen für technisch-physikalische Voraussetzungen wie auch für die tägliche Praxis der Leber-SBRT gegeben. Weiterhin werden radiobiologische Besonderheiten dieses Verfahrens dargestellt.ErgebnissePraktische Vorgaben werden für Patientenselektion, Bildgebung, Planung, Applikation, Bewegungsmanagement, Dosisdokumentation und Follow-up gegeben. Dosisempfehlungen für die kritischen Risikoorgane werden dargestellt.SchlussfolgerungDie SBRT stellt eine etablierte Behandlungsmethode für primäre und sekundäre Lebertumore dar und ist mit niedriger Morbidität assoziiert.

Support Vector Machine-Based Prediction of Local Tumor Control After Stereotactic Body Radiation Therapy for Early-Stage Non-Small Cell Lung Cancer

BACKGROUND Several prognostic factors for local tumor control probability (TCP) after stereotactic body radiation therapy (SBRT) for early stage non-small cell lung cancer (NSCLC) have been described, but no attempts have been undertaken to explore whether a nonlinear combination of potential factors might synergistically improve the prediction of local control. METHODS AND MATERIALS We investigated a support vector machine (SVM) for predicting TCP in a cohort of 399 patients treated at 13 German and Austrian institutions. Among 7 potential input features for the SVM we selected those most important on the basis of forward feature selection, thereby evaluating classifier performance by using 10-fold cross-validation and computing the area under the ROC curve (AUC). The final SVM classifier was built by repeating the feature selection 10 times with different splitting of the data for cross-validation and finally choosing only those features that were selected at least 5 out of 10 times. It was compared with a multivariate logistic model that was built by forward feature selection. RESULTS Local failure occurred in 12% of patients. Biologically effective dose (BED) at the isocenter (BED(ISO)) was the strongest predictor of TCP in the logistic model and also the most frequently selected input feature for the SVM. A bivariate logistic function of BED(ISO) and the pulmonary function indicator forced expiratory volume in 1 second (FEV1) yielded the best description of the data but resulted in a significantly smaller AUC than the final SVM classifier with the input features BED(ISO), age, baseline Karnofsky index, and FEV1 (0.696 ± 0.040 vs 0.789 ± 0.001, P<.03). The final SVM resulted in sensitivity and specificity of 67.0% ± 0.5% and 78.7% ± 0.3%, respectively. CONCLUSIONS These results confirm that machine learning techniques like SVMs can be successfully applied to predict treatment outcome after SBRT. Improvements over traditional TCP modeling are expected through a nonlinear combination of multiple features, eventually helping in the task of personalized treatment planning.