Sabine Levegrün

Value of 18F-Fluoro-2-Deoxy-d-Glucose-Positron Emission Tomography/Computed Tomography in Non–Small-Cell Lung Cancer for Prediction of Pathologic Response and Times to Relapse after Neoadjuvant Chemoradiotherapy

Purpose: To determine the value of combined positron emission tomography/computed tomography (PET/CT) during induction chemotherapy (CTx) followed by chemoradiotherapy (CTx/RTx) for non–small-cell lung cancer to predict histopathologic response in primary tumor and mediastinum and prognosis of the patient. Experimental Design: Fifty consecutive patients with locally advanced non–small-cell lung cancer received induction therapy and, if considered resectable, proceeded to surgery (37 of 50 patients). Patients had at least two repeated 18F-2-fluoro-2-deoxy-d-glucose (FDG)-PET/CT scans either before treatment (t0) or after induction CTx (t1) or CTx/RTx (t2). Variables from the PET/CT studies [e.g., lesion volume and corrected maximum standardized glucose uptake values (SUVmax,corr)] were correlated with histopathologic response (graded as 3, 2b, or 2a: 0%, >0-10%, or >10% residual tumor cells) and times to failure. Results: Primary tumors showed a percentage decrease in SUVmax,corr during induction significantly larger in grade 2b/3 than in grade 2a responding tumors (67% versus 34% at t1, 73% versus 49% at t2; both P < 0.005). SUVmax,corr at t2 was significantly correlated with histopathologic response in tumors smaller than the median volume (7.5 cm3; r = −0.54, P = 0.02). In the mediastinal lymph nodes, SUVmax,corr values at t2 predicted an ypN0 status with a sensitivity and specificity of 73% and 89%, respectively (SUVmax,corr threshold of 4.1, r = −0.54, P = 0.0005). Freedom from extracerebral relapse was significantly better in grade 2b/3 patients (86% at 16 months versus 20% in 2a responders; P = 0.003) and in patients with a greater percentage decrease in SUVmax,corr in the primary tumor at t2 in relation to t0 than in patients with lesser response (83% at 16 months versus 43%; P = 0.03 for cutoff points between 0.45 and 0.55). Conclusions: SUVmax,corr values from two serial PET/CT scans, before and after three chemotherapy cycles or later, allow prediction of histopathologic response in the primary tumor and mediastinal lymph nodes and have prognostic value.

gamma-H2AX foci formation in peripheral blood lymphocytes of tumor patients after local radiotherapy to different sites of the body: dependence on the dose-distribution, irradiated site and time from start of treatment.

Purpose: To evaluate the relationship between an estimated integral total body radiation dose delivered and phosphorylated histone H2AX protein (γ-H2AX) foci formation in peripheral blood lymphocytes of cancer patients. Material and methods: γ-H2AX formation was quantified as the mean number of foci per lymphocyte (NmeanH2AX) and the percentage of lymphocytes with ≥n foci. The integrated total body radiation dose was estimated from the dose volume histogram of patients body corrected for the proportion of the body scanned by computed tomography for 3D treatment planning. Results: There was a strong linear correlation between the mean number of γ-H2AX foci per lymphocyte in the peripheral blood sample and integrated total body radiation dose (r = 0.83, p < 0.0001). The slope of the relationship was dependent on the site of body irradiated. In comparison to chest irradiation with a slope of 8.7 ± 0.8 foci Gy−1, the slopes for brain, upper leg and pelvic sites were significantly shallower by −4.7, −4.3, and −3.8 Gy−1, respectively (p < 0.0001), while the slope for upper abdomen irradiation was significantly larger by 9.1 ± 2.6 Gy−1 (p = 0.0007). There was a slight time effect since the start of radiotherapy on the slopes of the in vivo dose responses leading to shallower slopes (−1.5 ± 0.7 Gy−1, p = 0.03) later (≥10 day) during radiotherapy. After in vitro irradiation, lymphocytes showed 10.41 ± 0.12 foci per Gy with no evidence of inter-individual heterogeneity. Conclusions: γ-H2AX measurements in peripheral lymphocytes after local radiotherapy allow the estimation of the applied integral body dose. The site and time dependence have to be considered.

Usability of semiautomatic segmentation algorithms for tumor volume determination

RATIONALE AND OBJECTIVES Tumor volume is an important parameter for clinical decision making. At present, semiautomatic image segmentation is not a standard for tumor volumetry. The aim of this work was to investigate the usability of semiautomatic algorithms for tumor volume determination. METHODS Semiautomatic region- and volume-growing, isocontour, snakes, hierarchical, and histogram-based segmentation algorithms were tested for accuracy, contour variability, and time performance. The test were performed on a newly developed organic phantom for the simulation of a human liver and liver metastases. The real tumor volumes were measured by water displacement. These measured volumes were used as the gold standard for determining the accuracy of the algorithms. RESULTS Variability of the segmented volumes ranging from 3.9 +/- 3.2% (isocontour algorithm) to 11.5 +/- 13.9% (hierarchical segmentation) was observed. The segmentation time per slice varied between 32 (volume-growing) and 72 seconds (snakes) on an IBM/RS6000 workstation. CONCLUSIONS Only the region-growing and isocontour algorithms have the potential to be used for tumor volumetry. However, further improvements of these algorithms are necessary before they can be placed into clinical use.

Radiation-Induced Changes of Brain Tissue after Radiosurgery in Patients with Arteriovenous Malformations: Dose/Volume-Response Relations

Purpose:To evaluate late radiation effects in the brain after radiosurgery of patients with cerebral arteriovenous malformations (AVMs) and to quantify dose/volume-response relations for radiation-induced changes of brain tissue identified on follow-up neuroimaging.Patients and Methods:Data from 73 AVM patients who had stereotactic Linac radiosurgery at DKFZ (German Cancer Research Center), Heidelberg, Germany, were retrospectively analyzed. The endpoint of radiation-induced changes of brain tissue on follow-up magnetic resonance (MR) neuroimaging (i.e., edema and blood-brain-barrier breakdown [BBBB]) was evaluated. Each endpoint was further differentiated into three levels with respect to the extent of the image change (small, intermediate, and large). A previous analysis of the data found correlation of the endpoints with several dose/volume variables (DV) derived from each patient’s dose distribution in the brain, including the mean dose in a volume of 20 cm3 (Dmean20) and the absolute brain volume (including the AVM target) receiving a dose of at least 12 Gy (V12). To quantify dose/volume-response relations, patients were ranked according to DV (i.e., Dmean20 and V12) and classified into four groups of equal size. For each group, the actuarial rates of developing the considered endpoints within 2.5 years after radiosurgery were determined from Kaplan-Meier estimates. The dose/volume-response curves were fitted with a sigmoid-shape logistic function and characterized by DV50, the dose for a 50% incidence, and the slope parameter k.Results:Dose/volume-response relations, based on two alternative, but correlated, dose distribution variables that are a function of both dose and volume, were observed for radiation-induced changes of brain tissue. DV50 values of fitted dose/volume-response curves for tissue changes of large extent (e.g., V1250 = 22.0 ± 2.6 cm3 and Dmean2050 = 17.8 ± 2.0 Gy for the combined endpoint of edema and/or BBBB) were significantly higher than those for small tissue changes (V1250 = 4.0 ± 0.3 cm3 and Dmean2050 = 7.6 ± 0.3 Gy).Conclusion:The derived dose/volume-response relations allow to quantitatively assess the risk of radiation-induced changes of brain tissue after radiosurgery in AVM patients. However, further understanding of the mechanism leading to brain tissue changes and their correlation with the desired obliteration is required. This knowledge will eventually help to optimize radiosurgical treatments in AVM patients.Ziel:Untersuchung später Strahlenfolgen im Gehirn nach stereotaktischer Einzeit-Hochdosisbestrahlung von Patienten mit zerebralen arteriovenösen Malformationen (AVM) und Quantifizierung der Dosis/Volumen-Wirkungs-Beziehungen von strahleninduzierten Normalgewebeveränderungen anhand von Magnetresonanz-(MR-)Bildgebung während der Nachsorge.Patienten und Methodik:Daten von 73 AVM-Patienten, die sich einer stereotaktischen Strahlenchirurgie am Linearbeschleuniger unterzogen hatten, wurden retrospektiv ausgewertet. Als Endpunkt wurden strahleninduzierte Normalgewebeveränderungen (d.h. Ödeme und Störungen der Blut-Hirn-Schranke) in MR-Bildgebung untersucht. Jeder dieser Endpunkte wurde hinsichtlich der Ausdehnung der Normalgewebeveränderung weiter in drei Stufen differenziert (gering, mittelgroß, groß). Eine vorangegangene Analyse der Daten konnte eine Korrelation der Endpunkte mit verschiedenen Dosis/Volumen-Variablen (DV) aufzeigen, die für jeden Patienten aus der Dosisverteilung im Gehirn berechnet wurden, wie z.B. die mittlere Dosis in einem Volumen von 20 cm3 (Dmean20) und das absolute Hirnvolumen (einschließlich des AVM-Targets), das eine Dosis von mindestens 12 Gy erhält (V12). Zur Quantifizierung der Dosis/Volumen-Wirkungs-Beziehungen wurden die Patienten nach aufsteigendem DV (d.h. Dmean20 und V12) sortiert und in vier gleich große Gruppen aufgeteilt. In jeder Gruppe wurden die aktuarischen Risiken für das Auftreten der betrachteten Endpunkte innerhalb von 2,5 Jahren nach Strahlenchirurgie gemäß Kaplan-Meier-Verfahren bestimmt. Der sigmoidale Verlauf der Dosis/Volumen-Wirkungs-Kurven wurde mit Hilfe einer logistischen Funktion angepasst und durch DV50, die Dosis für eine 50%ige Inzidenz, sowie den Steigungsparameter k charakterisiert.Ergebnisse:Strahleninduzierte Normalgewebeveränderungen im Gehirn zeigten eine Dosis/Volumen-Wirkungs-Beziehung, wobei die abhängige Variable eine Funktion von Dosis und Volumen war. Die DV50-Werte der angepassten Kurven für Normalgewebeveränderungen mit großer Ausdehnung (z.B. V1250 = 22,0 ± 2,6 cm3 und Dmean2050 = 17,8 ± 2,0 Gy für den kombinierten Endpunkt Ödeme und/oder Schrankenstörungen) waren signifikant höher als für Veränderungen mit geringer Ausdehnung (V1250 = 4,0 ± 0,3 cm3 und Dmean2050 = 7,6 ± 0,3 Gy).Schlussfolgerung:Die ermittelten Dosis/Volumen-Wirkungs-Beziehungen erlauben eine quantitative Abschätzung des Risikos für strahleninduzierte Normalgewebeveränderungen im Gehirn nach stereotaktischer Einzeit-Hochdosisbestrahlung von AVM-Patienten. Jedoch ist ein tieferes Verständnis der Ursache dieser Normalgewebeveränderungen und ihrer Korrelation mit der angestrebten Obliteration notwendig. Die genaue Kenntnis der Dosis/Volumen-Wirkungs-Beziehungen kann zukünftig zur Optimierung der Strahlentherapie bei AVM-Patienten beitragen.

Re-irradiation of recurrent head and neck carcinomas: comparison of robust intensity modulated proton therapy treatment plans with helical tomotherapy

BackgroundTo test the hypothesis that the therapeutic ratio of intensity-modulated photon therapy using helical tomotherapy (HT) for retreatment of head and neck carcinomas can be improved by robust intensity-modulated proton therapy (IMPT).MethodsComparative dose planning with robust IMPT was performed for 7 patients retreated with HT.ResultsOn average, HT yielded dose gradients steeper in a distance ≤ 7.5 mm outside the target (p<0.0001, F-test) and more conformal high dose regions down to the 50% isodose than IMPT. Both methods proved comparably robust against set-up errors of up to 2 mm, and normal tissue exposure was satisfactory. The mean body dose was smaller with IMPT.ConclusionsIMPT was found not to be uniformly superior to HT and the steeper average dose fall-off around the target volume is an argument pro HT under the methodological implementations used. However, looking at single organs at risk, the normal tissue sparing of IMPT can surpass tomotherapy for an individual patient. Therefore, comparative dose planning is recommended, if both methods are available.

Determination of target volumes for three-dimensional radiotherapy of cancer patients with a fuzzy system

Abstract Radiotherapy is an effective treatment for many cancer patients. The target volume to be irradiated is defined by the radiotherapist. In order to cure a patient, the target volume must comprise all potential tumor cells. However, the imaging techniques on which the process of target volume determination is based can visualize the gross tumor mass but not individual cells. This causes diagnostic uncertainties, leading to a fuzziness of the target volume. In order to assist the radiotherapist in the definition of the optimal target volume for an individual patient, a new approach based on Fuzzy Logic was developed that incorporates the fuzziness in the target volume definition: The radiotherapist defines a minimal target volume which surely contains tumor cells and a maximal target volume, outside of which no tumor cell spread is expected. The fuzziness region in between is processed by a knowledge-based fuzzy system. This system contains fuzzy sets and rules laid down by experienced radiotherapists. It is used to calculate the membership values of individual subvolumes in the fuzziness region with respect to the target volume. The result is a fuzzy target volume. An application of the subset defuzzification yields a crisp target volume with optimized extension which is proposed to the radiotherapist. The new approach was applied to test phantoms and clinical case examples.

Helical Tomotherapy for Whole-Brain Irradiation With Integrated Boost to Multiple Brain Metastases: Evaluation of Dose Distribution Characteristics and Comparison With Alternative Techniques

PURPOSE To quantitatively evaluate dose distribution characteristics achieved with helical tomotherapy (HT) for whole-brain irradiation (WBRT) with integrated boost (IB) to multiple brain metastases in comparison with alternative techniques. METHODS AND MATERIALS Dose distributions for 23 patients with 81 metastases treated with WBRT (30 Gy/10 fractions) and IB (50 Gy) were analyzed. The median number of metastases per patient (N(mets)) was 3 (range, 2-8). Mean values of the composite planning target volume of all metastases per patient (PTV(mets)) and of the individual metastasis planning target volume (PTV(ind met)) were 8.7 ± 8.9 cm(3) (range, 1.3-35.5 cm(3)) and 2.5 ± 4.5 cm(3) (range, 0.19-24.7 cm(3)), respectively. Dose distributions in PTV(mets) and PTV(ind met) were evaluated with respect to dose conformity (conformation number [CN], RTOG conformity index [PITV]), target coverage (TC), and homogeneity (homogeneity index [HI], ratio of maximum dose to prescription dose [MDPD]). The dependence of dose conformity on target size and N(mets) was investigated. The dose distribution characteristics were benchmarked against alternative irradiation techniques identified in a systematic literature review. RESULTS Mean ± standard deviation of dose distribution characteristics derived for PTV(mets) amounted to CN = 0.790 ± 0.101, PITV = 1.161 ± 0.154, TC = 0.95 ± 0.01, HI = 0.142 ± 0.022, and MDPD = 1.147 ± 0.029, respectively, demonstrating high dose conformity with acceptable homogeneity. Corresponding numbers for PTV(ind met) were CN = 0.708 ± 0.128, PITV = 1.174 ± 0.237, TC = 0.90 ± 0.10, HI = 0.140 ± 0.027, and MDPD = 1.129 ± 0.030, respectively. The target size had a statistically significant influence on dose conformity to PTV(mets) (CN = 0.737 for PTV(mets) ≤4.32 cm(3) vs CN = 0.848 for PTV(mets) >4.32 cm(3), P=.006), in contrast to N(mets). The achieved dose conformity to PTV(mets), assessed by both CN and PITV, was in all investigated volume strata well within the best quartile of the values reported for alternative irradiation techniques. CONCLUSIONS HT is a well-suited technique to deliver WBRT with IB to multiple brain metastases, yielding high-quality dose distributions. A multi-institutional prospective randomized phase 2 clinical trial to exploit efficacy and safety of the treatment concept is currently under way.

Estimation of complication probabilities after radiosurgery of AVM patients using a biological model

For the optimum use of radiotherapy, a precise knowledge of normal tissue tolerance data and complication probabilities is necessary. Mathematical algorithms were developed that attempt to predict the biological response of normal tissues to radiation, based on the physical dose distribution and radiobiological data. These biological models allow the calculation of normal tissue complication probabilities (NTCP). While biological models could potentially provide a valuable means to score and optimize treatment plans, their merit has not been proven yet and the underlying model parameters are affected with large uncertainties. However, studies that actually confront model predictions with clinical data are sparse.