Florian Sterzing

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.

Helical tomotherapy. Experiences of the first 150 patients in Heidelberg.

Background and Purpose:Helical tomotherapy was introduced into clinical routine at the Department of Radiation Oncology, University Hospital of Heidelberg, Germany, in July 2006. This report is intended to describe the experience with the first 150 patients treated with helical tomotherapy. Patient selection, time effort, handling of daily image guidance with megavoltage (MV) CT, and quality of radiation plans shall be assessed.Patients and Methods:Between July 2006 and May 2007, 150 patients were treated with helical tomotherapy in the University Hospital of Heidelberg. Mean age was 60 years with a minimum of 30 years and a maximum of 85 years. 79 of these patients received radiotherapy as a part of multimodal treatment pre- or postoperatively, 17 patients received treatment as a combined radiochemotherapy. 76% were treated with curative intent. Radiotherapy sites were central nervous system (n = 7), head and neck (n = 28), thoracic (n = 37), abdominal (n = 58) and skeletal system (n = 20). Most common tumor entities were prostate cancer (n = 28), breast cancer (n = 17), gastrointestinal tumors (n = 19), pharyngeal carcinoma (n = 14), lymphoma (n = 13), metastatic disease (bone n = 14, liver n = 6, lung n = 4, lymph node n = 2), sarcoma (n = 8), malignant pleural mesothelioma (n = 5), ovarian cancer treated with whole abdominal irradiation (n = 4), lung cancer (n = 3), skin malignancies (n = 3), chordoma (n = 2), meningioma (n = 2), one ependymoma and one medulloblastoma treated with craniospinal axis irradiation (n = 2), and others (n = 4). Nine patients were treated with single-fraction radiosurgery, nine with image-guided spinal reirradiation, and twelve patients were treated at multiple targets simultaneously. A pretreatment MV-CT scan was performed in 98.2% of the 3,026 fractions applied. After matching with the kilovoltage planning CT, corrections for translations and rotation around longitudinal axis (roll) were done.Results:Mean time on table was 24.8 min for the mentioned tumor entities with fractionated radiation, mean treatment time 10.7 min. Mean correction vector after MV-CT registration was 6.9 mm. With helical tomotherapy it was possible to achieve highly conformal dose distributions for targets of all sizes and multiple targets within one procedure. Image guidance with MV-CT allowed daily position correction and safe and precise treatment application. This was feasible even if the desired immobilization was not possible due to obesity, claustrophobia, pain, or neurologic or orthopedic impairment.Conclusion:Helical tomotherapy and daily image guidance with MV-CT could fast be introduced into daily clinical routine. This technique allows precise intensity-modulated radiotherapy (IMRT) in standard cases and offers new treatment options in a huge variety of difficult cases.Hintergrund und Ziel:Die helikale Tomotherapie wurde im Juli 2006 in der radioonkologischen Abteilung der Universitätsklinik Heidelberg in die klinische Routine eingeführt. Diese Arbeit soll die Erfahrungen der ersten 150 mit helikaler Tomotherapie behandelten Patienten beschreiben. Die Selektion der Patienten, Zeitaufwand, täglicher Gebrauch der Bildführung mittels Megavolt-(MV-)CT sowie die Qualität der Bestrahlungspläne sollen untersucht werden.Patienten und Methodik:Zwischen Juli 2006 und Mai 2007 wurden 150 Patienten mittels helikaler Tomotherapie im Universitätsklinikum Heidelberg behandelt. Das mittlere Alter betrug 60 Jahre mit einem Minimum von 30 Jahren und einem Maximum von 85 Jahren. 79 der Patienten erhielten eine Radiotherapie als Teil einer multimodalen Behandlung prä- oder postoperativ, 17 Patienten wurden einer kombinierten Radiochemotherapie unterzogen. 76% wurden in kurativer Absicht therapiert. Orte der Radiotherapieapplikation waren zentrales Nervensystem (n = 7), Kopf/Hals (n = 28), Thorax (n = 37), Abdomen (n = 58) und Skelettsystem (n = 20). Die häufigsten Tumorentitäten waren Prostatakarzinome (n = 28), Mammakarzinome (n = 17), gastrointestinale Tumoren (n = 19), Pharynxkarzinome (n = 14), Lymphome (n = 13), Metastasen (ossär n = 14, hepatisch n = 6, pulmonal n = 4, Lymphknoten n = 2), Sarkome (n = 8), maligne Pleuramesotheliome (n = 5), Ovarialkarzinome, die mittels Ganzabdomenbestrahlung behandelt wurden (n = 4), Bronchialkarzinome (n = 3), Hautmalignome (n = 3), Chordome (n = 2), Meningeome (n = 2), ein Ependymom und ein Medulloblastom, welche mittels Neuroachsenbestrahlung behandelt wurden, sowie andere Histologien (n = 4). Neun Patienten erhielten eine radiochirurgische Therapie in einer einzelnen Fraktion, neun Patienten eine bildgeführte spinale Rebestrahlung, und zwölf Patienten wurden an multiplen Targets gleichzeitig behandelt. Ein prätherapeutisches MV-CT wurde in 98,2% der 3 026 applizierten Fraktionen durchgeführt, und nach dem Matching wurden hierauf basierend Korrekturen für Translationen und Rotation um die Longitudinalachse („roll“) durchgeführt.Ergebnisse:Für die beschriebenen Tumorentitäten betrug die durchschnittliche Zeit auf dem Bestrahlungstisch bei fraktionierter Bestrahlung 24,8 min, die durchschnittliche Nettobehandlungszeit 10,7 min. Der mittlere Korrekturvektor nach MV-CT-Matching lag bei 6,9 mm. Mittels helikaler Tomotherapie war es möglich, hochkonformale Dosisverteilungen für Zielvolumina aller Größen oder multiple Zielvolumina in einer einzelnen Bestrahlungsprozedur zu erzielen. Dabei erlaubte die tägliche Bildführung mittels MV-CT eine sichere Positionskorrektur und präzise Durchführung der Therapie. Dies war auch möglich, wenn eine gewünschte Immobilisation aufgrund von Platzangst, Adipositas, Schmerzen oder neurologischer oder orthopädischer Begleiterkrankungen nicht vorgenommen werden konnte.Schlussfolgerung:Helikale Tomotherapie und tägliche Bildführung mittels MV-CT konnten schnell und erfolgreich in die klinische Routine eingeführt werden. Diese Technik ermöglicht die präzise und schonende Behandlung von Standardfällen mittels intensitätsmodulierter Strahlentherapie (IMRT) und eröffnet neue Behandlungsoptionen für schwierige Fälle.

Helical Tomotherapy as a New Treatment Technique for Whole Abdominal Irradiation

Purpose:To describe a new intensity-modulated radiotherapy (IMRT) technique using helical tomotherapy for whole abdominal irradiation (WAI) in patients with advanced ovarian cancer.Material and Methods:A patient with radically operated ovarian cancer FIGO stage IIIc was treated in a prospective clinical trial with WAI to a total dose of 30 Gy in 1.5-Gy fractions as an additional therapy after adjuvant platinum-based chemotherapy. The planning target volume (PTV) included the entire peritoneal cavity. PTV was adapted according to breathing motion as detected in a four-dimensional respiratory-triggered computed tomography (4D-CT). Inverse treatment planning was done with the Hi-Art tomotherapy planning station. Organs at risk (OARs) were kidneys, liver, bone marrow, spinal cord, thoracic and lumbosacral vertebral bodies, and pelvic bones. Daily control of positioning accuracy was performed with megavoltage computed tomography (MV-CT).Results:Helical tomotherapy enabled a very homogeneous dose distribution with excellent sparing of OARs and coverage of the PTV (V90 of 93.1%, V95 of 86.9%, V105 of 1.9%, and V110 of 0.01%). Mean liver dose was 21.57 Gy and mean kidney doses were 9.75 Gy and 9.14 Gy, respectively. Treatment could be performed in 18.1 min daily and no severe side effects occurred.Conclusion:Helical tomotherapy is feasible and fast for WAI. Tomotherapy enabled excellent coverage of the PTV and effective sparing of liver, kidneys and bone marrow.Ziel:Beschreibung der ersten klinischen Erfahrungen mit einer helikalen Tomotherapie als neuartiges Therapieverfahren für eine intensitätsmodulierte Ganzabdomenbestrahlung in der adjuvanten Therapie des fortgeschrittenen Ovarialkarzinoms.Material und Methodik:Eine Patientin mit Ovarialkarzinom im Stadium FIGO IIIc wurde im Rahmen einer prospektiven klinischen Studie nach radikaler Operation und sechs Zyklen adjuvanter platinhaltiger Chemotherapie zusätzlich mit einer Ganzabdomenbestrahlung mittels helikaler Tomotherapie behandelt. Die Gesamtdosis betrug 30 Gy mit einer wöchentlichen Fraktionierung von 5 × 1,5 Gy. Das Planungszielvolumen (PTV) umfasste die gesamte Peritonealhöhle unter Einschluss der paraaortalen und pelvinen Lymphabflusswege. Das Ausmaß des Zielvolumens wurde der Atembewegung auf Basis einer atemgetriggerten vierdimensionalen Computertomographie (4D-CT) angepasst. Es wurde mit dem Hi-Art-tomotherapy-Planungssystem invers geplant. Als Risikoorgane wurden Nieren, Leber, Rückenmark, Brustwirbelsäule, Lendenwirbelsäule und knöchernes Becken definiert. Die korrekte Patientenpositionierung wurde mittels Megavolt-Computertomographie (MV-CT) täglich kontrolliert.Ergebnisse:Mittels helikaler Tomotherapie konnten eine homogene Dosisverteilung, eine exzellente Schonung der Risikoorgane sowie eine ausgezeichnete Erfassung des PTV erreicht werden (V90: 93,1%, V95: 86,9%, V105: 1,9%, V110: 0,01%). Die mediane Dosis an der Leber betrug 21,57 Gy und an den Nieren jeweils 9,75 Gy und 9,14 Gy. Die tägliche Bestrahlungsdauer lag bei 18,1 min. Es traten keine schweren Nebenwirkungen CTC (Common Toxicity Criteria) Grad 3 oder 4 auf.Schlussfolgerung:Die Ganzabdomenbestrahlung mittels helikaler Tomotherapie ist machbar und in der klinischen Routine einsetzbar. Mit der helikalen Tomotherapie konnte eine exzellente Erfassung des PTV bei gleichzeitig sehr guter Schonung von Leber, Nieren und Knochenmark erreicht werden.

Highlights of the EORTC St. Gallen International Expert Consensus on the primary therapy of gastric, gastroesophageal and oesophageal cancer – Differential treatment strategies for subtypes of early gastroesophageal cancer

The 1st St. Gallen EORTC Gastrointestinal Cancer Conference 2012 Expert Panel clearly differentiated treatment and staging recommendations for the various gastroesophageal cancers. For locally advanced gastric cancer (≥T3N+), the preferred treatment modality was pre- and postoperative chemotherapy. The majority of panel members would also treat T2N+ or even T2N0 tumours with a similar approach mainly because pretherapeutic staging was considered highly unreliable. It was agreed that adenocarcinoma of the gastroesophageal junction (AEG) is classified best according to Siewert et al. Preoperative radiochemotherapy (RCT) is the preferred treatment for AEG type I and II tumours. For AEG type III, i.e. tumours which may be considered as gastric cancer, perioperative chemotherapy is the majority approach. For resectable squamous cell cancer of the oesophagus a clear majority recommended radiochemotherapy followed by surgery as optimal approach, irrespective of tumour size. In contrast, definitive RCT was judged appropriate for advanced tumours with extended lymph node involvement (N2) or for cancers of the upper oesophagus. Additional recommendations are presented on the use of endosonography, PET-CT scan and laparoscopy for staging and on the preferred approach to surgery.

Evaluating target coverage and normal tissue sparing in the adjuvant radiotherapy of malignant pleural mesothelioma: Helical tomotherapy compared with step-and-shoot IMRT

PURPOSE To evaluate the potential of helical tomotherapy in the adjuvant treatment of malignant pleural mesothelioma and compare target homogeneity, conformity and normal tissue dose with step-and-shoot intensity-modulated radiotherapy. METHODS AND MATERIALS Ten patients with malignant pleural mesothelioma who had undergone neoadjuvant chemotherapy with cisplatin and permetrexed followed by extrapleural pneumonectomy (EPP) were treated in our department with 54 Gy to the hemithorax delivered by step-and-shoot IMRT. A planning comparison was performed by creating radiation plans for helical tomotherapy. The different plans were compared by analysing target homogeneity using the homogeneity indices HI(max) and HI(min) and target conformity by using the conformity index CI(95). To assess target coverage and normal tissue sparing TV(90), TV(95) and mean and maximum doses were compared. RESULTS Both modalities achieved excellent dose distributions while sparing organs at risk. Target coverage and homogeneity could be increased significantly with helical tomotherapy compared with step-and-shoot IMRT. Mean dose to the contralateral lung could be lowered beyond 5 Gy. CONCLUSIONS Our planning study showed that helical tomotherapy is an excellent option for the adjuvant intensity-modulated radiotherapy of MPM. It is capable of improving target coverage and homogeneity.

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.

Radiobiological investigation of dose-rate effects in intensity-modulated radiation therapy.

Background and Purpose:Intensity-modulated radiation therapy (IMRT) has proven extraordinary capability in physical terms such as target conformity, dose escalation in the target volume, and sparing of neighboring organs at risk. The radiobiological consequences of the protracted dose delivery for cell survival and cell cycle progression are still unclear and shall be examined in this study.Material and Methods:Human lymphoblasts (TK6) and human melanoma cells (MeWo) were irradiated with protocols of increasing dose protraction. In addition, a new biophysical phantom was developed and used to transfer clinical IMRT plans to experimental cell irradiation. Clonogenic cell survival and cell cycle analysis were performed after various irradiation experiments.Results:In a first series of experiments, melanoma cells showed a highly significant increase of survival of 6.0% after protracted dose delivery of 2 Gy compared to conventional fast application with the same dose. Lymphoblastoid cells also showed a significant increase of survival of 2.2%. Experiments with patient plans in the phantom confirmed the trend of increased cell survival after protracted dose delivery. Cells were irradiated at 13 points in four different IMRT plans. In comparison to irradiation with application of the same dose in a classic four-field box, a significantly increased survival of 5.1% (mean value) was determined.Conclusion:Even at fraction times of 15–30 min the protracted dose delivery increases the survival rates in cell culture. The altered survival rates indicate the importance of the dose rate in the effectivity of IMRT. Besides physical parameters the consideration of biological factors might contribute to the optimization of IMRT in the future.Hintergrund und Ziel:Die intensitätsmodulierte Strahlentherapie (IMRT) ist ein modernes Radiotherapieverfahren, welches unter physikalischen Gesichtspunkten wie der Zielkonformität, Dosiseskalation und Schonung von Risikostrukturen hervorragende Ergebnisse erzielen kann. Doch die strahlenbiologischen Konsequenzen für Zellüberleben und Zellzyklusprogression, die sich aus der protrahierten Dosisapplikation ergeben könnten, sind noch unklar und sollen in dieser Arbeit untersucht werden.Material und Methodik:Humane Lymphoblasten (TK6) und humane Melanomzellen (MeWo) wurden mit Protokollen ansteigender Dosisprotrahierung bestrahlt. Zudem wurde ein neuartiges biophysikalisches Phantom entwickelt, welches die Übertragung klinischer IMRT-Pläne in ein vielseitiges experimentelles Setup ermöglicht. Klonogenes Zellüberleben sowie Zellzyklusprogression nach verschiedenen Bestrahlungsexperimenten wurden untersucht.Ergebnisse:In einer ersten Versuchsreihe zeigten die Melanomzellen ein signifikant um 6,0% erhöhtes Zellüberleben, wenn 2 Gy stark protrahiert appliziert wurden, verglichen mit schneller herkömmlicher Bestrahlung. Auch die Lymphoblasten zeigten ein um 2,2% signifikant erhöhtes Überleben. Die Experimente im Phantom mit Patientenplänen bestätigten den Trend des erhöhten Überlebens nach Dosisprotrahierung. Die Zellen wurden an 13 verschiedenen Punkten in vier IMRT-Plänen bestrahlt. Im Vergleich zur Bestrahlung mit der gleichen Dosis in einer konventionellen Vierfelderbox war das Überleben nach IMRT durchschnittlich um 5,1% erhöht.Schlussfolgerung:Selbst bei Fraktionszeiten von 15–30 min führt die protrahierte Dosisapplikation zu einem erhöhten Zellüberleben in Zellkultur. Die veränderten Überlebensraten zeigen die Bedeutung der Dosisrate für die Effektivität der IMRT. Neben physikalischen Parametern der Planbeurteilung müssen auch biologische Parameter zur weiteren Optimierung der IMRT herangezogen werden.

Influence of intra-fractional breathing movement in step-and-shoot IMRT

Efforts have been made to extend the application of intensity-modulated radiotherapy to a variety of organs. One of the unanswered questions is whether breathing-induced organ motion may lead to a relevant over- or underdosage, e.g., in treatment plans for the irradiation of lung cancer. Theoretical considerations have been made concerning the different kinds of IMRT but there is still a lack of experimental data. We examined 18 points in a fraction of a clinical treatment plan of a NSCLC delivered in static IMRT with a new phantom and nine ionization chambers. Measurements were performed at a speed of 12 and 16 breathing cycles per minute. The dose differences between static points and moving target points ranged between -2.4% and +5.5% (mean: +0.2%, median: -0.1%) when moving with 12 cycles min(-1) and between -3.6% and +5.0% (mean: -0.4%, median: -0.6%) when moving with 16 cycles min(-1). All differences of measurements with and without movements were below 5%, with one exception. In conclusion, our results underline that at least in static IMRT breathing effects (concerning target dose coverage) due to interplay effects between collimator leaf movement and target movement are of secondary importance and will not reduce the clinical value of IMRT in the step-and-shoot technique for irradiation of thoracic targets.

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.

DYNAMIC JAWS AND DYNAMIC COUCH IN HELICAL TOMOTHERAPY

PURPOSE To investigate the next generation of helical tomotherapy delivery with dynamic jaw and dynamic couch movements. METHODS AND MATERIALS The new technique of dynamic jaw and dynamic couch movements is described, and a comparative planning study is performed. Ten nasopharyngeal cancer patients with skull base infiltration were chosen for this comparison of longitudinal dose profiles using regular tomotherapy delivery, running-start-stop treatment, and dynamic jaw and dynamic couch delivery. A multifocal simultaneous integrated boost concept was used (70.4Gy to the primary tumor and involved lymph nodes; 57.4Gy to the bilateral cervical lymphatic drainage pathways, 32 fractions). Target coverage, conformity, homogeneity, sparing of organs at risk, integral dose, and radiation delivery time were evaluated. RESULTS Mean parotid dose for all different deliveries was between 24.8 and 26.1Gy, without significant differences. The mean integral dose was lowered by 6.3% by using the dynamic technique, in comparison with a 2.5-cm-field width for regular delivery and 16.7% with 5-cm-field width for regular delivery. Dynamic jaw and couch movements reduced the calculated radiation time by 66% of the time required with regular 2.5-cm-field width delivery (199 sec vs. 595 sec, p < 0.001). CONCLUSIONS The current delivery mode of helical tomotherapy produces dose distributions with conformal avoidance of parotid glands, brain stem, and spinal cord. The new technology with dynamic jaw and couch movements improves the plan quality by reducing the dose penumbra and thereby reducing the integral dose. In addition, radiation time is reduced by 66% of the regular delivery time.