Entwicklung eines service-orientierten und workflow-basierten Verfahrens zur automatisierten patientenübergreifenden Analyse von radioonkologischen Bild- und Bestrahlungsplanungsdaten

Einleitung Retrospektive Auswertungen klinischer Routinedaten gewinnen zunehmend an Bedeutung in der Strahlentherapie. Daher werden in der Strahlentherapie vermehrt Forschungsdatenbanken für die Zusammenführung der häufig stark verteilten heterogenen Daten aufgebaut. Die Zusammenführung der Daten ist jedoch nur der erste Schritt in Rich- tung Forschung. Die eigentliche Herausforderung besteht in der Analyse dieser heterogenen Daten. Es müssen Methoden entwickelt werden, um Bilddaten in die datenbankbasier- ten Analysen miteinzubeziehen. Retrospektive Analysen werden in der Radioonkologie überwiegend manuell durchgeführt. Daher spielen die Automatisierung und moderne Analysetechniken eine immer wichtigere Rolle. Fragestellung Das übergeordnete Ziel dieser Arbeit ist die Zusammenführung von hetero- genen, verteilten radioonkologischen Daten mit verschiedenen radioonkologischen Analy- setools zur Vereinfachung und Automatisierung von patientenübergreifenden bildbasierten retrospektiven Auswertungen in der Strahlentherapie. Zum Erreichen dieser Zielsetzung sollen im Rahmen dieser Arbeit eine zentrale radioonkologische Forschungsdatenbank und eine service-orientierte workflow-basierte Analyseplattform implementiert werden. An- schließend soll anhand verschiedener radioonkologischer Fragestellungen gezeigt werden, dass mit Hilfe dieser beiden Plattformen patientenübergreifende Analysen von Bild- und Bestrahlungsplanungsdaten automatisiert durchgeführt und dadurch vereinheitlicht und vereinfacht werden können. Ergebnisse Das erste Ziel war der Aufbau einer zentralen radioonkologischen Forschungs- plattform. Im Rahmen eines europäischen Forschungsprojekts wurde zunächst eine zen- trales Studiendokumentationssystem für die Partikeltherapie eingeführt, das nach Ende des Projekts zur zentralen radioonkologischen Forschungsdatenbank der Radioonkologie Heidelberg ausgebaut wurde. In der zentralen Forschungsdatenbank werden alle relevan- ten Daten inklusive Bild- und Bestrahlungsplanungsdaten aus verschiedensten klinischen Informationssystemen automatisiert zusammengeführt und durch ein Dokumentationsteam vervollständigt, um sie Klinikern und Wissenschaftlern für wissenschaftliche Auswertungen zur Verfügung stellen zu können. Das zweite Ziel war die Implementierung einer service-orientierten workflow-basierten Analyseplattform. Die Analyseplattform wurde auf Basis von existierenden Analysetools, die als Web Services zur Verfügung gestellt wurden, und unter Einsatz eines Workflow Management Systems realisiert und an die zentrale Forschungsdatenbank angebunden. Dadurch können kombinierte Analysen von radioonkologischen Bild- und Bestrahlungspla- nungsdaten sowie klinischen Daten automatisiert und standardisiert durchgeführt werden. Das dritte Ziel war der Nachweis der Machbarkeit solcher automatisierten Auswertungen im Rahmen eines Proof-of-Concept-Projekts. Hierzu wurde eine typische radioonkologi- sche Beispielfragestellung ausgewählt und realisiert. Dabei konnte gezeigt werden, dass mit Hilfe der Forschungsdatenbank und Analyseplattform eine vollständig automatisierte Rezidivanalyse bei Partikeltherapie-Patienten mit einem Gliom durchgeführt werden kann. Das vierte Ziel waren der Einsatz und die Weiterentwicklung der Forschungsdatenbank und Analyseplattform im Rahmen von drei realen radioonkologischen Forschungsprojekten. Im ersten Projekt konnte gezeigt werden, dass eine patientenübergreifende Dosis-Volumen- Analyse mit Hilfe der Analyseplattform auch für größere Patientenkollektive durchgeführt werden kann. Im zweiten und dritten Projekt konnte gezeigt werden, dass Planvergleichs- studien von zwei bzw. drei verschiedenen Bestrahlungstechniken patientenübergreifend automatisiert und standardisiert durchgeführt werden können. Diskussion Durch den Einsatz einer Forschungsdatenbank als zentrale Datenquelle wird der Zugriff auf klinische Daten vereinfacht und retrospektive Auswertungen können we- sentlich einfacher durchgeführt werden. Von technischer Seite konnte gezeigt werden, dass service-orientierte Technologien auch im Bereich der Bilddatenanalyse der Radioonkologie genutzt werden können. Aufgrund der modularen und standardisierten Systemarchitektur ist der in dieser Arbeit vorgestellte service-orientierte Ansatz erweiterbar und auf beliebige medizinische Bereiche wie z.B. die Radiologie oder Onkologie im Allgemeinen aber auch andere medizinische Fachbereiche übertragbar. Es konnte aber auch gezeigt werden, dass die Hoffnung, durch sorgfältige Analysen kli- nischer Routinedaten neue Erkenntnisse zu gewinnen, durch die klinischen Realitäten begrenzt sind. Aus verschiedensten Gründen kann es schwierig sein, auch aus einer großen Datenbasis eine ausreichende Anzahl von Fällen zu extrahieren, um darauf aufbauend statistisch signifikante Auswertungen durchführen zu können. Diese Erkenntnis sollte in Zukunft das Bewusstsein schärfen, wie wichtig eine lückenlose Erfassung der Daten ist. Service-orientierte und workflow-basierte Ansätze werden bisher überwiegend im Bereich der Bioinformatik verwendet, um wissenschaftliche Auswertungen automatisiert durch- führen zu können. Es gibt jedoch auch erste Bestrebungen, diese Ansätze auch für die Analyse von medizinischen Bilddaten zu verwenden, bisher jedoch nicht im Bereich der Strahlentherapie. Darüber hinaus ist die Anbindung einer Forschungsdatenbank als zentrale Datenquelle und zugleich Wissensbasis ebenfalls noch neu. Schlussfolgerung Insgesamt werden retrospektive Analysen von umfangreichen hetero- genen Datenbeständen in der Radioonkologie durch die im Rahmen dieser Arbeit ent- wickelte service-orientierte workflow-basierte Analyseplattform in Kombination mit der zentralen radioonkologischen Forschungsdatenbank wesentlich einfacher, da sowohl die Datenbeschaffung als auch die Datenanalyse automatisiert und zentralisiert und damit vereinheitlicht werden. In dieser Arbeit wurde eine System geschaffen, mit dem es möglich ist, automatisiert und effizient radioonkologische Daten zu analysieren. Dadurch sinkt der Aufwand für solche Auswertungen drastisch. Somit ist die retrospektive Auswertung umfangreicher radioonkologischer Routinedatenbestände ein Stück näher gerückt und aufwendige Plan- vergleichsstudien können effizienter durchgeführt werden. Dadurch kann die klassische evidenzbasierte Radioonkologie langfristig durch die retrospektive Analyse umfangreicher radioonkologischer Datenbestände unterstützt werden

Analyzing human decisions in IGRT of head-and-neck cancer patients to teach image registration algorithms what experts know

Background: In IGRT of deformable head-and-neck anatomy, patient setup corrections are derived by rigid registration methods. In practice, experienced radiation therapists often correct the resulting vectors, thus indicating a different prioritization of alignment of local structures. Purpose of this study is to transfer the knowledge experts apply when correcting the automatically generated result (pre-match) to automated registration. Methods: Datasets of 25 head-and-neck-cancer patients with daily CBCTs and corresponding approved setup correction vectors were analyzed. Local similarity measures were evaluated to identify the criteria for human corrections with regard to alignment quality, analogous to the radiomics approach. Clustering of similarity improvement patterns is applied to reveal priorities in the alignment quality. Results: The radiation therapists prioritized to align the spinal cord closest to the high-dose area. Both target volumes followed with second and third highest priority. The bony pre-match influenced the human correction along the crania-caudal axis. Based on the extracted priorities, a new rigid registration procedure is constructed which is capable of reproducing the corrections of experts. Conclusions: The proposed approach extracts knowledge of experts performing IGRT corrections to enable new rigid registration methods that are capable of mimicking human decisions. In the future, the deduction of knowledge-based corrections for different cohorts can be established automating such supervised learning approaches

Clinical outcome after particle therapy for meningiomas of the skull base: toxicity and local control in patients treated with active rasterscanning

Background: Meningiomas of the skull base account for 25–30% of all meningiomas. Due to the complex structure of the cranial base and its close proximity to critical structures, surgery is often associated with substantial morbidity. Treatment options include observation, aggressive surgical intervention, stereotactic or conventional radiotherapy. In this analysis we evaluate the outcome of 110 patients with meningiomas of the skull base treated with particle therapy. It was performed within the framework of the “clinical research group heavy ion therapy” and supported by the German Research Council (DFG, KFO 214). Methods: Between May 2010 and November 2014, 110 Patients with skull base meningioma were treated with particle radiotherapy at the Heidelberg Ion Therapy Center (HIT). Primary localizations included the sphenoid wing (n = 42), petroclival region (n = 23), cavernous sinus (n = 4), sella (n = 10) and olfactory nerve (n = 4). Sixty meningiomas were benign (WHO °I); whereas 8 were high-risk (WHO °II (n = 7) and °III (n = 1)). In 42 cases histology was not examined, since no surgery was performed. Proton (n = 104) or carbon ion (n = 6) radiotherapy was applied at Heidelberg Ion Therapy Center (HIT) using raster-scanning technique for active beam delivery. Fifty one patients (46.4%) received radiotherapy due to tumor progression, 17 (15.5%) after surgical resection and 42 (38.2%) as primary treatment. Results: Median follow-up in this analysis was 46,8 months (95% CI 39,9–53,7; Q1-Q3 34,3–61,7). Particle radiotherapy could be performed safely without toxicity-related interruptions. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered excellent overall local control rates with 100% progression-free survival (PFS) after 36 months and 96.6% after 60 months. Median PFS was not reached due to the small number of events. Histology significantly impacted PFS with superior PFS after 5 years for low-risk tumors (96.6% vs. 75.0%, p = 0,02). Overall survival was 96.2% after 60 months and 92.0% after 72 months from therapy. Of six documented deaths, five were definitely not and the sixth probably not meningioma-related. Conclusion Particle radiotherapy is an excellent treatment option for patients with meningiomas of the skull base and can lead to long-term tumor control with minimal side effects. Other prospective studies with longer follow-up will be necessary to further confirm the role of particle radiotherapy in skull base meningioma

Evaluation of particle radiotherapy for the re-irradiation of recurrent intracranial meningioma

Background: With the advance of modern irradiation techniques, the role of radiotherapy (RT) for intracranial meningioma has increased significantly throughout the past years. Despite that tumor’s generally favorable outcome with local control rates of up to 90% after ten years, progression after RT does occur. In those cases, re-irradiation is often difficult due to the limited radiation tolerance of the surrounding tissue. The aim of this analysis is to determine the value of particle therapy with its better dose conformity and higher biological efficacy for re-irradiating recurrent intracranial meningioma. It was performed within the framework of the “clinical research group heavy ion therapy” and funded by the German Research Council (DFG, KFO 214). Methods: Forty-two patients treated with particle RT (protons (n = 8) or carbon ions (n = 34)) for recurrent intracranial meningioma were included in this analysis. Location of the primary lesion varied, including skull base (n = 31), convexity (n = 5) and falx (n = 6). 74% of the patients were categorized high-risk according to histology with a WHO grading of II (n = 25) or III (n = 6), in the remaining cases histology was either WHO grade I (n = 10) or unknown (n = 1). Median follow-up was 49,7 months. Results: In all patients, re-irradiation could be performed safely without interruptions due to side effects. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered good overall local control rates with 71% progression-free survival (PFS) after 12 months, 56,5% after 24 months and a median PFS of 34,3 months (95% CI 11,7–56,9). Histology had a significant impact on PFS yielding a median PFS of 25,7 months (95% CI 5,8–45,5) for high-risk histology (WHO grades II and III) while median PFS was not reached for low-risk tumors (WHO grade I) (p = 0,03). Median time to local progression was 15,3 months (Q1-Q3 8,08–34,6). Overall survival (OS) after re-irradiation was 89,6% after 12 months and 71,4% after 24 months with a median OS of 61,0 months (95% CI 34,2–87,7). Again, WHO grading had an effect, as median OS for low-risk patients was not reached whereas for high-risk patients it was 45,5 months (95% CI 35,6–55,3). Conclusion: Re-irradiation using particle therapy is an effective method for the treatment of recurrent meningiomas. Interdisciplinary decision making is necessary to guarantee best treatment for every patient

Primary adenoid cystic carcinoma of the trachea: clinical outcome of 38 patients after interdisciplinary treatment in a single institution

Background: Primary adenoid cystic carcinomas (ACCs) of the trachea are rare tumors of the central bronchial system. In patients presenting with unresectable tumors, severe comorbidities, or incomplete surgical resection, definitive radiotherapy is currently the recommended treatment. Irradiation with carbon ions (C12) has shown promising local control (LC) and survival rates in cases of ACCs of the head and neck. No data on the therapeutic efficacy of C12 radiotherapy in treating tracheal ACC has been published. Methods: All patients with histologically confirmed ACC of the trachea treated with surgery and/or radiation treatment at Heidelberg University Hospital between 1991 and 2017 were included in this analysis. Patient and treatment characteristics, short- and long-term toxicity after radiotherapy, overall survival (OS), freedom from local progression (FFLP), and freedom from distant progression (FFDP) were prospectively acquired and retrospectively analyzed. Results: Thirty-eight patients (23 women and 15 men) with a median age of 51 were treated by surgery (n = 20) and/or radiotherapy with either C12 (n = 7) or photons (n = 24). Of these patients, 61% presented with locally advanced (stage 4) ACC. The median follow-up for all patients was 74.5 months. The 5-year OS for all patients was 95% (10-year: 81%). The 5-year FFLP and FFDP were 96% (10-year: 83%) and 69% (10-year: 53%), respectively. In patients who underwent surgery alone, the 5-year OS was 100% (10-year: 80%). The 5-year FFLP and FFDP were 100% (10-year: 100%) and 80% (10-year: 60%), respectively. In patients who underwent radiotherapy alone, the 5-year OS was 100% (10-year: 83%). The 5-year FFLP and FFDP were 88% (10-year: 44%) and 67% (10-year: 34%), respectively. In patients who received multi-modal treatment including surgery and adjuvant radiotherapy, the 5-year OS was 84% (10-year: 84%). The 5-year FFLP was 100% (10-year: 100%) and the 5-year FFDP was 65% (10-year, 65%). Conclusions: The long-term prognosis is favorable if surgery is performed. In cases of an incomplete resection, good OS can still be achieved following adjuvant radiotherapy. For radiotherapy, irradiation with C12 shows promising first results. However, more data is needed to prove the long-term advantage of C12 over photons. Trial registration: The ethics committee of the Heidelberg University Hospital approved the retrospective data analysis (S-174/2019)

Do Increased Doses to Stem-Cell Niches during Radiation Therapy Improve Glioblastoma Survival?

Background and Purpose. The reasons for the inevitable glioblastoma recurrence are yet understood. However, recent data suggest that tumor cancer stem cells (CSCs) in the stem-cell niches, with self-renewing capacities, might be responsible for tumor initiation, propagation, and recurrence. We aimed to analyze the effect of higher radiation doses to the stem-cell niches on progression-free survival (PFS) and overall survival (OS) in glioblastoma patients. Materials and Methods. Sixty-five patients with primary glioblastoma treated with radiation therapy were included in this retrospective analysis. The SVZ and DG were segmented on treatment planning magnetic resonance imaging, and the dose distributions to the structures were calculated. The relationship of dosimetry data and survival was evaluated using the Cox regression analysis. Results. Conventionally fractionated patients (n=54) who received higher doses (Dmean ≥ 40 Gy) to the IL SVZ showed improved PFS (8.5 versus 5.2 months; p=0.013). Furthermore, higher doses (Dmean ≥ 30 Gy) to the CL SVZ were associated with increased PFS (10.1 versus 6.9 months; p=0.025). Conclusion. Moderate higher IL SVZ doses (≥40 Gy) and CL SVZ doses (≥30 Gy) are associated with improved PFS. Higher doses to the DG, the second stem-cell niche, did not influence the survival. Targeting the potential cancer stem cells in the SVZ might be a promising treatment approach for glioblastoma and should be addressed in a prospective randomized trial

Intensity Modulated Radiotherapy (IMRT) + Carbon Ion Boost for Adenoid Cystic Carcinoma of the Minor Salivary Glands in the Oral Cavity

Background: Adenoid cystic carcinoma (ACC) are more common in the minor salivary glands (MiSGs) than the major salivary glands, and are characterized by slow tumor progression and frequently local recurrence. The main treatment option is surgery followed by combined radiotherapy. Methods: A retrospective analysis contained 67 patients with ACC of MiSGs in the oral cavity who underwent surgery followed by radiotherapy. The median cumulative IMRT dose was 50 Gy followed by 24 Gy for carbon ion (C12) boost. Median follow-up was 40 months. Results: Median 5-years overall survival (OS), progression-free survival (PFS) and local disease-free survival (LDFS) rates were 85.5%, 57.4% and 74.9%. Median time until progression was detected was 32 months (range: 2⁻205 months). Early grade ≥3 mucositis, dermatitis, and dysphagia were detected in 52.2%, 7.5% and 11.9% respectively. Besides common toxicities, two patients (3.0%) developed grade 3 toxicities with osteoradionecrosis of the jaw after 18 and 66 months. Higher-grade late toxicity (CTCAE grade 4) was not detected. No treatment-related death was detected. Conclusions: Our results demonstrate that postoperative combined radiotherapy with IMRT plus C12 boost seems to be a feasible and effective treatment method in ACC of MiSGs in the oral cavity, with good control and survival rates and adequate toxicity

High-sensitivity cardiac troponin T determines all-cause mortality in cancer patients: a single-centre cohort study

Aims: Cardio-oncology is a growing interdisciplinary field which aims to improve cardiological care for cancer patients in order to reduce morbidity and mortality. The impact of cardiac biomarkers, echocardiographic parameters, and cardiological assessment regarding risk stratification is still unclear. We aimed to identify potential parameters that allow an early risk stratification of cancer patients. Methods and results: In this cohort study, we evaluated 930 patients that were admitted to the cardio-oncology outpatient clinic of the University Hospital Heidelberg from January 2016 to January 2019. We performed echocardiography, including Global Longitudinal Strain (GLS) analysis and measured cardiac biomarkers including N-terminal pro brain-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T levels (hs-cTnT). Most patients were suffering from breast cancer (n = 450, 48.4%), upper gastrointestinal carcinoma (n = 99, 10.6%) or multiple myeloma (n = 51, 5.5%). At the initial visit, we observed 86.7% of patients having a preserved left ventricular ejection fraction (LVEF >50%). At the second follow up, still 78.9% of patients showed a preserved LVEF. Echocardiographic parameters or elevation of NT-proBNP did not significantly correlate with all-cause mortality (ACM) (logistic regression LVEF <50%: P = 0.46, NT-proBNP: P = 0.16) and failed to identify high-risk patients. In contrast, hs-cTnT above the median (≥7 ng/L) was an independent marker to determine ACM (multivariant logistic regression, OR: 2.21, P = 0.0038) among all included patients. In particular, hs-cTnT levels before start of a chemotherapy were predictive for ACM. Conclusions: Based on our non-selected cohort of cardio-oncological patients, hs-cTnT was able to identify patients with high mortality by using a low cutoff of 7 ng/L. We conclude that measurement of hs-cTnT is an important tool to stratify the risk for mortality of cancer patients before starting chemotherapy

Connection of European particle therapy centers and generation of a common particle database system within the European ULICE-framework

<p>Abstract</p> <p>Background</p> <p>To establish a common database on particle therapy for the evaluation of clinical studies integrating a large variety of voluminous datasets, different documentation styles, and various information systems, especially in the field of radiation oncology.</p> <p>Methods</p> <p>We developed a web-based documentation system for transnational and multicenter clinical studies in particle therapy. 560 patients have been treated from November 2009 to September 2011. Protons, carbon ions or a combination of both, as well as a combination with photons were applied. To date, 12 studies have been initiated and more are in preparation.</p> <p>Results</p> <p>It is possible to immediately access all patient information and exchange, store, process, and visualize text data, any DICOM images and multimedia data. Accessing the system and submitting clinical data is possible for internal and external users. Integrated into the hospital environment, data is imported both manually and automatically. Security and privacy protection as well as data validation and verification are ensured. Studies can be designed to fit individual needs.</p> <p>Conclusions</p> <p>The described database provides a basis for documentation of large patient groups with specific and specialized questions to be answered. Having recently begun electronic documentation, it has become apparent that the benefits lie in the user-friendly and timely workflow for documentation. The ultimate goal is a simplification of research work, better study analyses quality and eventually, the improvement of treatment concepts by evaluating the effectiveness of particle therapy.</p