Meinhard Nevinny-Stickel

Reproducibility of Patient Positioning for Fractionated Extracranial Stereotactic Radiotherapy Using a Double-Vacuum Technique

Background and Purpose:Precise reproducible patient positioning is a prerequisite for conformal fractionated radiotherapy. A fixation system based on double-vacuum technology is presented which can be used for conventional as well as hypofractionated stereotactic extracranial radiotherapy.Material and Methods:To form the actual vacuum mattress, the patient is pressed into the mattress with a vacuum foil which can also be used for daily repositioning and fixation. A stereotactic frame can be positioned over the region of interest on an indexed base plate. Repositioning accuracy was determined by comparing daily, pretreatment, orthogonal portal images to the respective digitally reconstructed radiographs (DRRs) in ten patients with abdominal and pelvic lesions receiving extracranial fractionated (stereotactic) radiotherapy. The three-dimensional (3-D) vectors and 95% confidence intervals (CI) were calculated from the respective deviations in the three axes. Time required for initial mold production and daily repositioning was also determined.Results:The mean 3-D repositioning error (187 fractions) was 2.5 ± 1.1 mm. The largest single deviation (10 mm) was observed in a patient treated in prone position. Mold production took an average of 15 min (10–30 min). Repositioning times are not necessarily longer than using no positioning aid at all.Conclusion:The presented fixation system allows reliable, flexible and efficient patient positioning for extracranial stereotactic radiotherapy.Hintergrund und Ziel:Voraussetzung für eine konformale fraktionierte Strahlentherapie ist eine präzise reproduzierbare Positionierung des Patienten und des Zielvolumens. Vorgestellt wird ein auf dem Doppelvakuumprinzip basierendes Fixationssystem, das sowohl für konventionelle als auch extrakranielle stereotaktische Bestrahlungen eingesetzt werden kann.Material und Methodik:Mittels einer Fixationsfolie, mit der er auch zusätzlich fixiert werden kann, wird der Patient vor der Abformung in die Vakuummatratze hineingepresst. Eine exakt auf einer indexierten Bodenplatte positionierbare Plexiglashaube dient als stereotaktischer Rahmen. Bei zehn Patienten mit Zielvolumina im Abdomen und Becken wurden vor jeder Bestrahlung orthogonale digitale Verifikationsaufnahmen angefertigt. Diese wurden mit den digital rekonstruierten Röntgenbildern (DRRs) des dreidimensionalen (3-D) Planungssystems verglichen. Aus den Abweichungen der drei Raumrichtungen wurden die 3-D-Vektoren als Maß für die Repositionierungsgenauigkeit errechnet.Ergebnisse:Der Mittelwert der für alle Patienten errechneten 3-D-Vektoren (187 Fraktionen) betrug 2,5 ± 1,1 mm. Der mit 10 mm größte 3-D-Vektor wurde bei einem in Bauchlage bestrahlten Patienten beobachtet. Die initiale Abformung dauerte im Durchschnitt 15 min (10–30 min). Der tägliche zeitliche Lagerungsaufwand am Bestrahlungsgerät ist nur unwesentlich länger als ohne Fixationshilfe.Schlussfolgerung:Das vorgestellte Fixierungssystem ermöglicht eine zuverlässige, flexible und effiziente Patientenpositionierung für die stereotaktische Bestrahlung extrakranieller Tumoren.

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.

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.

A Simple and Non-Invasive Vacuum Mouthpiece-Based Head Fixation System for High Precision Radiotherapy

Purpose: To demonstrate why conventional non-invasive mouthpiece-based fixation has not achieved the expected accuracy and to suggest a solution of the problem. Patients and Methods: The Vogele Bale Hohner (VBH) head holder is a non-invasive vacuum mouthpiece-based head fixation system. Feasibility and repositioning accuracy were evaluated by portal image analysis in 12 patients with cranial tumors intended for stereotactic procedures, fixated with the newest version (VBH HeadFix-ARC®). Results: Portal image analysis (8 patients evaluated in 2-D, 4 patients in 3-D) showed that even in routine external beam radiation therapy, treatment can be applied to within a mean 2-D and 3-D accuracy of under 2 mm (SD 0.92 mm and 1.2 mm, respectively) with cost and repositioning time per patient and patient comfort comparable to that of common thermoplastic masks. Conclusion: These preliminary results show that high repositioning accuracy does not rule out simple and quick application and patient comfort. Paramount, however, is tensionless repositioning via the vacuum mouthpiece.Ziel: Fixationssysteme, die auf konventionellen (nicht Vakuum-)Mundstücken basieren, erreichen oftmals nicht die erwartete Genauigkeit. Die vorliegende Arbeit beschäftigt sich mit den möglichen Ursachen und bietet entsprechende Lösungen. Patienten und Methoden: Der Vogele-Bale-Hohner-(VBH-)Head-Holder ist ein nicht invasives, auf einem Vakuummundstück (Abbildung 1) basierendes Kopffixationssystem (Abbildungen 2 und 3). Bei zwölf Patienten mit kraniellen Tumoren wurde mit der neuesten Version (VBH HeadFix-ARC®) die Repositionsgenauigkeit mittels Portal Imaging untersucht. Ergebnisse: Die Portal-Imaging-Auswertung (acht Patienten in 2-D, vier Patienten in 3-D) bestätigte, dass eine Bestrahlung im Kopfbereich auch in der klinischen Routine mit einer mittleren Genauigkeit von unter 2 mm (Standardabweichung 0,92 bzw. 1,2 mm) appliziert werden kann, während Kosten, Repositionsdauer und Akzeptanz der Patienten vergleichbar sind mit denen thermoplastischer Masken. Schlussfolgerung: Diese vorläufigen Ergebnisse zeigen, dass eine hohe Repositionierungsgenauigkeit ein einfaches, schnelles und für den Patienten angenehmes System nicht ausschließt. Ausschlaggebend ist die spannungsfreie Lagerung mittels Vakuummundstück.

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.

Compensating for Tumor Motion by a 6-Degree-of-Freedom Treatment Couch: Is Patient Tolerance an Issue?

PURPOSE To determine whether patients could tolerate the motion of a robotic couch that compensates for breathing-induced tumor motion. METHODS AND MATERIALS A total of 10 healthy subjects and 23 radio-oncology patients underwent simulated extracranial stereotactic radiotherapy (two 30-min sessions) on a robotic couch programmed to follow a fictitious tumor trajectory of 20x5x5 mm (cranio-caudal, left-right, and anterior-posterior directions, respectively) while rotating 2 degrees around a cranio-caudal axis at a frequency of 5 seconds per loop. RESULTS No session had to be interrupted and no nausea was induced. However, one patient refused the second session due to general deterioration and not all patients could keep their arms elevated for the entire session. CONCLUSIONS Our findings showed that most patients tolerated compensatory couch motion and that motion sickness should not pose a problem in the investigation of this tumor-tracking method.

Optimized Conformal Paraaortic Lymph Node Irradiation is not Associated with Enhanced Renal Toxicity

Background and Purpose:For patients with gynecologic carcinomas, irradiation of paraaortic lymph nodes (PLNs) is a routine treatment concept. Planning target volumes (PTVs) individually optimized by radiation field delineations along the big vessels permit the inclusion of at least 97% of potentially involved PLNs. However, this novel treatment technique might increase radiation-induced nephrotoxicity. Therefore, the actual incidence of kidney damage after PLN irradiation has to be assessed in order to validate the safety of this treatment concept.Patients and Methods:19 patients were treated with irradiation alone (50.4 Gy; 5 × 1.8 Gy/week) and monitored for up to 90 months. Functional renal parameters, namely renal plasma flow (RPF) and glomerular filtration rate (GFR), were assessed by dynamic renal scintigraphy. Additionally, patients were clinically observed (i.e., hypertension, proteinuria) and calculations of normal-tissue complication probability (NTCP) values for nonuniform kidney irradiation were performed using the Lyman-Wolbarst algorithm.Results:Two patients with anticipated moderate NTCP values (12.6% and 8.7%) showed slightly impaired RPF rates at 12, 24, and after 48 months of follow-up. Only one patient in the subgroup showing NTCP values > 50% (n = 9) developed a notable impairment of renal RPF. However, all patients including those with elevated complication probabilities exhibited neither impaired GFR nor clinically apparent symptoms related to a loss of functioning renal tissue from 12 to > 48 months post irradiation.Conclusion:Conformal irradiation of retroperitoneal lymph nodes with individual PTV delineation appears not to be associated with clinically relevant functional impairment of the kidneys.Hintergrund und Ziel:Die Behandlung von Patientinnen mit gynäkologischen Tumoren beinhaltet häufig die Bestrahlung der paraaortalen Lymphknoten (PLNs). Durch eine individuelle Anpassung des Planungszielvolumens (PTV) an den Verlauf der großen abdominalen Gefäße können mindestens 97% aller potentiell befallenen PLNs behandelt werden. Die dadurch z.T. vergrößerten PTVs könnten aber mit einer gesteigerten Inzidenz für eine radiogene Nephropathie einhergehen. Um die Sicherheit dieser neuen Bestrahlungstechnik zu überprüfen, wurde das tatsächliche Auftreten von radiogenen Nephropathien nach solchen PLN-Bestrahlungen untersucht.Patienten und Methodik:19 Patientinnen mit gynäkologischen Tumoren, die eine Bestrahlung der PLNs (50,4 Gy; 5 × 1,8 Gy/Woche) ohne Chemotherapie in der Klinik der Autoren erhielten, wurden bis zu 90 Monate nachbeobachtet. Mittels seitengetrennter Nierenclearence wurden renaler Plasmafluss (RPF) und glomeruläre Filtrationsrate (GFR) bestimmt und die Patientinnen regelmäßig klinisch untersucht (u.a. Blutdruck, Proteinurie). Außerdem wurden für jede Patientin aus den dreidimensionalen Bestrahlungsplänen für beide Nieren NTCP-Werte (Wahrscheinlichkeit von Normalgewebskomplikationen) nach dem Lyman-Wolbarst-Algorithmus berechnet.Ergebnisse:Zwei Patientinnen mit moderaten NTCP-Werten (12,6% und 8,7%) wiesen nach 12, 24 und 48 Monaten eine leichte Störung des RPF auf. Nur eine Patientin aus der Gruppe mit NTCP-Werten > 50% (n = 9) entwickelte eine ausgeprägtere Störung des RPF. Keine Patientin zeigte eine Störung der GFR oder klinische Symptome einer Nierenschädigung in der Zeit von 12 bis > 48 Monate nach der Bestrahlung.Schlussfolgerung:Die konformale Bestrahlung der PLNs mit einem individuellen, dem Verlauf der großen Gefäße angepassten PTV führte im eigenen Patientenkollektiv in keinem Fall zu einer klinisch relevanten radiogenen Nephropathie.

Standard- versus individuell geplantes Bestrahlungsfeld bei Radiotherapie infradiaphragmaler Lymphknotenstationen

PURPOSE In prophylactic irradiation of infradiaphragmatic lymphatic nodes, the width of the paraaortic and pelvic field is given by a line joining the tips of the transverse processes of the 11th thoracic to the 4th lumbar vertebra from where the field boundary follows a straight line to the most lateral point of the acetabulum as seen in simulation film. Another way to build the field border is to project the lateral contours of the large abdominal vessels from T1-weighted coronal MR images of the abdomen on the simulator radiographs and add a 2-cm margin along the vessels delineated. In our study, we compared both methods as to full enclosure of paraaortic and pelvic lymphatics or nodal miss. MATERIAL AND METHODS Abdominal CT scans of 81 patients with involvement of paraaortic lymph node regions were examined with maximum lymph node sizes of 2.5 cm. The distance from the center of the appropriate vertebra to the lateral lymph node contour referring to the transverse process as well as to the outside contour of the aorta on the left and the vena cava on the right side, respectively, the iliac vessels were measured from T12 through S1. At the level of the hip joint the measurement point was given by the caput femoris. RESULTS Our measurement prove that 10% of the lymph nodes were found lateral from the transverse processes of the thoracic and lumbar vertebras and 12% outside the 2-cm safety margin from the lateral contour of the large abdominal vessels. CONCLUSION Our data show, that the customary fields for infradiaphragmatic lymphatic nodes have so far not been able to enclose all retroperitoneal and pelvic lymph nodes with certainty.ZusammenfassungZielsetzungBei der adjuvanten Bestrahlung infradiaphragmaler Lymphknotenstationen wird die Feldgrenze entweder durch die Wirbelkörperquerfortsätze bzw. durch die Verbindungslinie zwischen dem Querfortsatz des Lendenwirbelkörpers 4 und dem Dach des Acetabulums gebildet oder durch maßstabsgerechte Projektion der großen Gefäße inklusive eines 2 cm breiten Sicherheitssaumes in die Simulationsaufnahme mittels koronarer MRI-Bilder ermittelt. In unserer Studie haben wir beide Methoden bezüglich der lymphknotentreffsicherheit miteinander verglichen.Material und MethodeAbdominelle CT-Schichtaufnahmen von 81 Patienten mit retroperitonealem Lymphknotenbefall von maximal 2,5 cm Lymphknotengröße wurden untersucht. Der Abstand vom jeweiligen Wirbelkörpermittelpunkt zu den lateralen Lymphknotenkonturen in bezug auf die Querfortsätze sowie auf die Außenkontur der Aorta links und der Vena cava rechts bzw. des iliakalen Gefäßbündels von Brustwirbelkörper 12 bis Sakralwirbelkörper 1 wurde gemessen. In Höhe des Femurkopfes ergab sich die Meßgrenze durch die Femurkopfmitte.ErgebnisseDie Meßdaten ergaben für die oben angeführten Meßhöhen (Brustwirbelkörper 12 bis Femurkopf) beidseitig, daß sich 10% der Lymphknoten außerhalb der Querfortsätze und 12% außerhalb des 2 cm breiten Sicherheitsabstandes von der Gefäßaußenkontur befinden.SchlußfolgerungUnsere Meßergebnisse zeigen, daß die bisher verwendeten Bestrahlungsfelder der infradiaphragmalen Lymphknotenstationen nicht ausreichend bemessen waren.AbstractPurposeIn prophylactic irradiation of infradiaphragmatic lymphatic nodes, the width of the paraaortic and pelvic field is given by a line joining the tips of the transverse processes of the 11th thoracic to the 4th lumbar vertebra from where the field boundary follows a straight line to the most lateral point of the acetabulum as seen in simulation film. Another way to build the field border is to project the lateral contours of the large abdominal vessels from T1-weighted coronal MR images of the abdomen on the simulator radiographs and add a 2-cm margin along the vessels delineated. In our study, we compared both methods as to full enclosure of paraaortic and pelvic lymphatics or nodal miss.Material and MethodsAbdominal CT scans of 81 patients with involvement of paraaortic lymph node regions were examined with maximum lymph node sizes of 2.5 cm. The distance from the center of the appropriate vertebra to the lateral lymph node contour referring to the transverse process as well as to the outside contour of the aorta on the left and the vena cava on the right side, respectively, the iliac vessels were measured from T12 through S1. At the level of the hip joint the measurement point was given by the caput femoris.ResultsOur measurements prove that 10% of the lymph nodes were found lateral from the transverse processes of the thoracic and lumbar vertebras and 12% outside the 2-cm safety margin from the lateral contour of the large abdominal vessels.ConclusionOur data show, that the customary fields for infradiaphragmatic lymphatic nodes have so far not been able to enclose all retroperitoneal and pelvic lymph nodes with certainty.

Sex Differences in Renal Proximal Tubular Cell Homeostasis

Studies in human patients and animals have revealed sex-specific differences in susceptibility to renal diseases. Because actions of female sex hormones on normal renal tissue might protect against damage, we searched for potential influences of the female hormone cycle on basic renal functions by studying excretion of urinary marker proteins in healthy human probands. We collected second morning spot urine samples of unmedicated naturally ovulating women, postmenopausal women, and men daily and determined urinary excretion of the renal tubular enzymes fructose-1,6-bisphosphatase and glutathione-S-transferase-α Additionally, we quantified urinary excretion of blood plasma proteins α1-microglobulin, albumin, and IgG. Naturally cycling women showed prominent peaks in the temporal pattern of urinary fructose-1,6-bisphosphatase and glutathione-S-transferase-α release exclusively within 7 days after ovulation or onset of menses. In contrast, postmenopausal women and men showed consistently low levels of urinary fructose-1,6-bisphosphatase excretion over comparable periods. We did not detect changes in urinary α1-microglobulin, albumin, or IgG excretion. Results of this study indicate that proximal tubular tissue architecture, representing a nonreproductive organ-derived epithelium, undergoes periodical adaptations phased by the female reproductive hormone cycle. The temporally delimited higher rate of enzymuria in ovulating women might be a sign of recurring increases of tubular cell turnover that potentially provide enhanced repair capacity and thus, higher resistance to renal damage.

Comparison of standard and individually planned infradiaphragmatic fields in irradiation of retroperitoneal lymph nodes.

PURPOSE In prophylactic irradiation of infradiaphragmatic lymphatic nodes (LN), the width of the paraaortic and pelvic field is given by a line joining the tips of the transverse processes of the 11th thoracic to the 4th lumbar vertebrae. Then the field boundary follows a straight line to the most lateral point of the acetabulum seen on the simulation film. Another method of setting the field border is to project the lateral contours of the large abdominal vessels from T(1)-weighted coronal MR images of the abdomen onto the simulator radiographs and add a 2-cm margin along the so delineated vessels. In our study, we compared both methods as to full enclosure of paraaortic and pelvic lymphatics or nodal miss. MATERIAL AND METHODS Abdominal CT scans of 81 patients with involvement of paraaortic lymph node regions with LN sizes not exceeding 2.5 cm were examined. The distance from the center of the appropriate vertebra to the center of the most lateral lymph node was referred to the transverse process as well as to the outside contour of the aorta on the left and the vena cava on the right side. Respectively, the LN were measured referenced to the iliac vessels from the 5th lumbar through to the 2nd sacral vertebra. At the level of the hip joint the distance was measured from the midline as determined by a line through the center of the sacrum, perpendicular to a line connecting center of both femoral heads. RESULTS Our measurements showed that lymph nodes do occur (1) lateral to the transverse processes of the thoracic and lumbar vertebrae as well as (2) outside the 2-cm safety margin from the lateral contour of the large abdominal vessels. CONCLUSION These data clearly show that the traditional fields for radiation of infradiaphragmatic lymphatic nodes have not been large enough to enclose almost all retroperitoneal and pelvic lymph nodes with certainty. We recommend an expansion of the fields.