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Objective The goal of this retrospective study is the evaluation of risk factors for postoperative neurological deficits after petroclival meningioma (PCM) surgery with special focus on standard craniotomies. Materials and methods One-hundred-fifty-eight patients were included in the study, of which 133 patients suffered from primary and 25 from recurrent PCM. All patients were operated on and evaluated concerning age, tumor size, histology, pre- and postoperative cranial nerve (CN) deficits, morbidity, mortality, and surgical complications. Tumor-specific features—e.g., consistency, surface, arachnoid cleavage, and location—were set in a four-grade classification system that was used to evaluate the risk of CN deficits and tumor resectability. Results After primary tumor resection, new CN deficits occurred in 27.3% of patients. Preoperative ataxia improved in 25%, whereas 10% developed new ataxia. Gross total resection (GTR) was achieved in 59.4%. The morbidity rate, including hemiparesis, shunt-dependence, postop-hemorrhage, and tracheostomy was 22.6% and the mortality rate was 2.3%. In recurrent PCM surgery, CN deficits occurred in 16%. GTR could be achieved in three cases. Minor complications occurred in 20%. By applying the proposed new classification system to patients operated via standard craniotomies, the best outcome was observed in type I tumor patients (soft tumor consistency, smooth surface, plane arachnoid cleavage, and unilateral localization) with GTR in 78.7% (p Conclusion Standard craniotomies as the retrosigmoid or subtemporal/pterional approaches are often used for the resection of PCMs. Whether these approaches are sufficient for GTR—and avoidance of new neurological deficits—depends mainly on the localization and intrinsic tumor-specific features.

Purpose: The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C).Experimental Design: Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms.Results: We identified a 7-gene signature consisting of the three individual genes HILPDA, CD24, TCF3, and one metagene combining the highly correlated genes SERPINE1, INHBA, P4HA2, and ACTN1. The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci = 0.82), which was successfully validated (ci = 0.71). The signature showed improved performance compared with clinical parameters alone (ci = 0.66) and with a previously published model including hypoxia-associated genes and cancer stem cell markers (ci = 0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation (P < 0.001).Conclusions: We have identified and validated the first hypothesis-based gene signature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification. Clin Cancer Res; 24(6); 1364–74. ©2018 AACR.

Table S1 Analyzed genes of the hypothesis-driven gene set. Table S2 Programs and packages used for evaluation. Figure S1 Results of repeated 3-fold cross validation for LRC. Figure S2 Mean oob ci depending of the signature size for LRC. Figure S3 Importance score for genes associated with LRC. Table S3 Increasing robustness by including highly correlated genes. Figure S4 Patient stratification by the 7-gene signature for LRC. Figure S5 Patient stratification by the 7-gene signature and clinical parameters for LRC. Table S4 Multivariable Cox regression of OS. Figure S6 Patient stratification by the 7-gene signature and clinical parameters for OS. Table S5 Multivariable Cox regression of DM. Figure S7 Patient stratification by the 7-gene signature and clinical parameters for DM. Table S6 Means and standard deviations of the 7-gene signature gene expressions. Table S7 Comparison of gene expressions between patient groups. Table S8 Hyper-parameters for feature selection algorithms and predictive models. Table S9 Patient characteristics of all patients. Figure S8 Identification of the final gene signature.

Bei der Behandlung von Hirntumoren padiatrischer und erwachsener Patienten stellt die Strahlentherapie eine regelhaft angewendete Behandlungsmodalitat dar. Die Protonentherapie ist eine innovative Art der Bestrahlung, mit der die therapeutische Breite weiter verbessert werden soll. Aufgrund der technisch-physikalischen Besonderheiten kann mittels Protonentherapie eine bessere Normalgewebsschonung erreicht werden, wahrend die Zielvolumenerfassung i. d. R. sehr ahnlich zur Standard-Photonentherapie ist. Dabei wird die biologische Strahlenwirkung unter Berucksichtigung eines Korrekturfaktors von 1,1 („relative biological effectiveness“, RBE) als vergleichbar angenommen. Bei kindlichen Hirntumoren ist die Indikation zur Protonentherapie i. d. R. aufgrund der erhohten Strahlenempfindlichkeit des sich noch entwickelnden Nervengewebes sowie aufgrund bereits vorliegender vergleichender Daten gegeben, die eine geringere Toxizitat der Protonentherapie im Vergleich zu Photonen zeigen. Padiatrische Tumoren werden moglichst in klinischen Studien oder zumindest analog nach der Empfehlung von Referenzzentren behandelt. Trotz der zunehmend breiteren Anwendung der Protonentherapie bei Erwachsenen weltweit fehlen noch belastbare Studiendaten zur geringeren Toxizitat im Normalgewebe fur die meisten Tumorarten. Es muss untersucht werden, ob und in welchen Patientengruppen sich die veranderte Dosisverteilung in klinisch relevante Vorteile ubersetzt und damit den erhohten Aufwand bzw. die vermehrten Kosten einer Protonentherapie rechtfertigt. Translationaler Forschungsbedarf besteht auch bei der Identifikation von besonders profitierenden Subgruppen und der Integration biologischer Erkenntnisse, insbesondere zur Variabilitat der Protonen-RBE, in die optimierte Bestrahlungsplanung.

Background High-dose hypofractionated radiotherapy should theoretically result in a deviation from the typical linear-quadratic shape of the cell survival curve beyond a certain threshold dose, yet no evidence for this hypothesis has so far been found in clinical data of stereotactic body radiotherapy treatment (SBRT) for early-stage non-small cell lung cancer (NSCLC). A pragmatic explanation is a larger α/β ratio than the conventionally assumed 10 Gy. We here attempted an estimation of the α/β ratio for NSCLC treated with SBRT using individual patient data. Materials and methods We combined two large retrospective datasets, yielding 1294 SBRTs (≤10 fractions) of early stage NSCLC. Cox proportional hazards regression, a logistic tumor control probability model and a biologically motivated Bayesian cure rate model were used to estimate the α/β ratio based on the observed number of local recurrences and accounting for tumor size. Results A total of 109 local progressions were observed after a median of 17.7 months (range 0.6–76.3 months). Cox regression, logistic regression of 3 year tumor control probability and the cure rate model yielded best-fit estimates of α/β = 12.8 Gy, 14.9 Gy and 12–16 Gy (depending on the prior for α/β), respectively, although with large uncertainties that did not rule out the conventional α/β = 10 Gy. Conclusions Clinicians can continue to use the simple LQ formalism to compare different SBRT treatment schedules for NSCLC. While α/β = 10 Gy is not ruled out by our data, larger values in the range 12–16 Gy are more probable, consistent with recent meta-regression analyses.

Aktuell gibt es 36 bekannte Blutgruppensysteme Klinisch besonders bedeutsam ist das AB0-System, da bereits Anti-A-und Anti-B-Antikorper ab dem ersten Lebensjahr im Plasma existieren („Isoagglutinine“, Tab. 48.1). AB0-inkompatible Transfusionen fuhren zu akuten hamolytischen Transfusionsreaktionen und konnen todlich sein

Background Large variation regarding prescription and dose inhomogeneity exists in stereotactic body radiation therapy (SBRT) for early-stage non-small cell lung cancer. The aim of this modeling study was to identify which dose metric correlates best with local tumor control probability to make recommendations regarding SBRT prescription. Methods and Materials We combined 2 retrospective databases of patients with non-small cell lung cancer, yielding 1500 SBRT treatments for analysis. Three dose parameters were converted to biologically effective doses (BEDs): (1) the (near-minimum) dose prescribed to the planning target volume (PTV) periphery (yielding BEDmin); (2) the (near-maximum) dose absorbed by 1% of the PTV (yielding BEDmax); and (3) the average between near-minimum and near-maximum doses (yielding BEDave). These BED parameters were then correlated to the risk of local recurrence through Cox regression. Furthermore, BED-based prediction of local recurrence was attempted by logistic regression and fast and frugal trees. Models were compared using the Akaike information criterion. Results There were 1500 treatments in 1434 patients; 117 tumors recurred locally. Actuarial local control rates at 12 and 36 months were 96.8% (95% confidence interval, 95.8%-97.8%) and 89.0% (87.0%-91.1%), respectively. In univariable Cox regression, BEDave was the best predictor of risk of local recurrence, and a model based on BEDmin had substantially less evidential support. In univariable logistic regression, the model based on BEDave also performed best. Multivariable classification using fast and frugal trees revealed BEDmax to be the most important predictor, followed by BEDave. Conclusions BEDave was generally better correlated with tumor control probability than either BEDmax or BEDmin. Because the average between near-minimum and near-maximum doses was highly correlated to the mean gross tumor volume dose, the latter may be used as a prescription target. More emphasis could be placed on achieving sufficiently high mean doses within the gross tumor volume rather than the PTV covering dose, a concept needing further validation.

Background and purpose To evaluate the quality of life (QoL) of patients with inoperable non-small cell lung cancer treated with conventionally fractionated radiotherapy (CF) vs. continuous hyperfractionated accelerated radiotherapy weekend-less (CHARTWEL). Material and methods The largest monocentric subgroup of the phase III CHARTWEL trial was analyzed up to three years after randomization. QoL was assessed with the European Organization for Research and Treatment of Cancer QoL Core Questionnaire (QLQ-C30) and lung cancer module (QLQ-LC13) and compared using linear mixed models. QoL interrelations with recurrence, metastasis, and death were explored by multi-state modeling. Results 160 patients (98%) provided at least one QoL assessment. Average treatment differences of CF vs. CHARTWEL over three years were −5.4 points (95%CI [−13.6,2.8], p = 0.19) in global QoL, 11.9 ([2.8,21.0], p = 0.01) in fatigue, 13.4 ([3.5,23.3], p = 0.009) in pain, 10.5 ([1.3,19.6], p = 0.03) in dyspnea, and 5.2 ([−2.7,13.0], p = 0.19) in dysphagia. At 12 months, the probabilities of being disease-free with good, good or moderate, any global QoL, or alive were 5.1%, 20.3%, 34.2%, 54.4% under CF and 10.4%, 21.0%, 37.5%, 65.3% under CHARTWEL. Conclusions Over three years, QoL was similar or more favorable under CHARTWEL compared to CF. Modeling QoL together with disease states provided additional insight into treatment comparisons.

// Tareq A. Juratli 1, 2 , Christian Thiede 3 , Mara V.A. Koerner 1 , Shilpa S. Tummala 1 , Dirk Daubner 4 , Ganesh M. Shankar 1 , Erik A. Williams 5 , Maria Martinez-Lage 5 , Silke Soucek 2 , Katja Robel 2 , Tristan Penson 1 , Mechthild Krause 6, 7, 8 , Steffen Appold 6, 7, 8 , Matthias Meinhardt 9 , Thomas Pinzer 2 , Julie J. Miller 10 , Dietmar Krex 2, 7 , Heather A. Ely 11 , Ian M. Silverman 11 , Jason Christiansen 11 , Gabriele Schackert 2, 7 , Hiroaki Wakimoto 1 , Matthias Kirsch 2, 7, * , Priscilla K. Brastianos 12, * and Daniel P. Cahill 1, * 1 Translational Neuro-Oncology Laboratory, Department of Neurosurgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts, USA 2 Department of Neurosurgery, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 3 Department of Medicine I, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 4 Institute of Neuroradiology, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 5 Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA 6 Institute of Radiooncology, Helmholtz-Zentrum Dresden - Rossendorf, Dresden, Germany 7 German Cancer Consortium (DKTK) Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany 8 Department of Radiation Oncology and OncoRay, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 9 Institute of Pathology, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany 10 Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA 11 Ignyta, Inc., San Diego, California, USA 12 Department of Medicine, Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA * These authors have contributed equally to this work Correspondence to: Daniel P. Cahill, email: cahill@mgh.harvard.edu Priscilla K. Brastianos, email: PBRASTIANOS@mgh.harvard.edu Matthias Kirsch, email: Matthias.kirsch@uniklinikum-dresden.de Keywords: meningioma; telomere; heterogeneity; rearrangements; fusion Received: August 18, 2017 Accepted: October 30, 2017 Published: November 24, 2017 ABSTRACT Background: Recent studies have reported mutations in the telomerase reverse transcriptase promoter ( TERT p) in meningiomas. We sought to determine the frequency, clonality and clinical significance of telomere gene alterations in a cohort of patients with progressive/higher-grade meningiomas. Methods: We characterized 64 temporally- and regionally-distinct specimens from 26 WHO grade III meningioma patients. On initial diagnoses, the meningiomas spanned all WHO grades (3 grade I, 13 grade II and 10 grade III). The tumor samples were screened for TERT p and ATRX/DAXX mutations, and TERT rearrangements. Additionally, TERT p was sequenced in a separate cohort of 19 patients with radiation-associated meningiomas. We examined the impact of mutational status on patients’ progression and overall survival. Results: Somatic TERT p mutations were detected in six patients (6/26 = 23%). Regional intratumoral heterogeneity in TERT p mutation status was noted. In 4 patients, TERT p mutations were detected in recurrent specimens but not in the available specimens of the first surgery. Additionally, a TERT gene fusion ( LPCAT1-TERT ) was found in one sample. In contrary, none of the investigated samples harbored an ATRX or DAXX mutation. In the cohort of radiation-induced meningiomas, TERT p mutation was detected in two patients (10.5%). Importantly, we found that patients with emergence of TERT p mutations had a substantially shorter OS than their TERT p wild-type counterparts (2.7 years, 95% CI 0.9 – 4.5 years versus 10.8 years, 95% CI 7.8 -12.8 years, p=0.003). Conclusions: In progressive/higher-grade meningiomas, TERT p mutations are associated with poor survival, supporting a model in which selection of this alteration is a harbinger of aggressive tumor development. In addition, we observe spatial intratumoral heterogeneity of TERT p mutation status, consistent with this model of late emergence in tumor evolution. Thus, early detection of TERT p mutations may define patients with more aggressive meningiomas. Stratification for TERT alterations should be adopted in future clinical trials of progressive/higher-grade meningiomas.

Background and purpose Pronounced early side effects have been suggested to be a positive prognostic factor in patients undergoing chemo-radio-therapy (CRT) for head and neck squamous cell carcinomas (HNSCC). We assessed the utility of positron emission tomography (PET) during treatment to analyze the correlation of 18F-fluorodeoxyglucose (FDG) uptake in off target structures within the irradiated volume with outcome. Material and methods Two independent cohorts of patients with locally advanced HNSCC, both treated within prospective clinical imaging trials with curatively intended CRT were retrospectively analyzed. The exploratory cohort included 50, the independent validation cohort 26 patients. Uptake of FDG in mucosa and submucosal soft tissues (MST) as well as in other structures was assessed at week 4 during treatment. Considered endpoints were local tumor control (LC) and overall survival (OS). The prognostic value of FDG uptake on the endpoints was measured by the concordance index (ci) using univariate and multivariate Cox regression analyses based on the continuous variables of the exploratory cohort. Results In the exploratory cohort FDG uptake in MST was prognostic for LC (hazard ratio HR=0.23, p =0.025) and OS (HR=0.30, p =0.003) in univariate analyses. These findings remained significant upon multivariate testing (LC HR=0.14, p =0.011; OS HR=0.20, p =0.001) and were confirmed in the validation cohort for LC (HR=0.15, p =0.034) and OS (HR=0.17, p =0.003). Also the SUV mean threshold of MST that was generated within the exploratory cohort (2.375) yielded significant differences in OS ( p =0.006) and a statistical trend for LC ( p =0.078) when applied to the validation cohort. Conclusions FDG uptake in normal tissues within the irradiated volume measured by PET during treatment has significant prognostic value in HNSCC. This effect may potentially be of use for personalized treatment adaptation.

Die Inzidenz von Hirnmetastasen nimmt im Zuge immer besserer Moglichkeiten der Behandlung maligner Tumoren zu. Als Primartumoren werden meistens Bronchialkarzinome, Mammakarzinome und maligne Melanome diagnostiziert. Die Behandlung erfordert ein interdisziplinares Vorgehen und bemisst sich nach verschiedenen Faktoren wie der Histologie des Primartumors, der Gesamtprognose, der Anzahl der Hirnmetastasen und der extrazerebralen Metastasierung. Infrage kommen eine Tumorresektion oder Radiochirurgie als lokale Therapie, Ganzhirnbestrahlung als regionaler Therapieansatz, Chemo- oder Immuntherapie als systemische Behandlung sowie supportive Masnahmen als symptomatischer Behandlungsansatz. Die Indikationsstellung und das Vorgehen werden jeweils naher erlautert. Daruber hinaus erfolgt eine Einordnung des Stellenwerts der Therapieansatze.

Objective To validate the impact of HPV status, cancer stem cell (CSC) marker expression and tumour hypoxia status in patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who received postoperative radiotherapy. The results of the exploration cohort have previously been reported by the German Cancer Consortium Radiation Oncology Group (DKTK-ROG; Lohaus et al., 2014; Linge et al., 2016). Materials and methods For 152 patients with locally advanced HNSCC the impact of HPV16 DNA status, CSC marker expression and hypoxia-associated gene signatures on outcome of postoperative radiotherapy were retrospectively analysed. Out of them, 40 patients received postoperative radiochemotherapy. Cox models presented in a previous study were validated using the concordance index as a performance measure. The primary endpoint of this study was loco-regional control. Results were compared to those previously reported by DKTK-ROG. Results Loco-regional control, freedom from distant metastases and overall survival were inferior to the previously reported cohort. Despite of this, the prognostic value of the combination of HPV infection status, CSC marker expression ( SLC3A2 ) and tumour hypoxia status could be validated in univariate analyses using an independent validation cohort. For multivariate models, the concordance index was between 0.58 and 0.69 in validation, indicating a good prognostic performance of the models. The inclusion of CD44 and the 15-gene hypoxia signature moderately improved the performance compared to a baseline model without CSC markers or hypoxia classifiers. Conclusions The HPV status, CSC marker expression of CD44 and SLC3A2 as well as hypoxia status are potential prognostic biomarkers for patients with locally advanced HNSCC treated by postoperative radiotherapy.

Item does not contain fulltext Introduction: Inter-observer variability (IOV) in target volume delineation is a well-documented source of geometric uncertainty in radiotherapy. Such variability has not yet been explored in the context of adaptive re-delineation based on imaging data acquired during treatment. We compared IOV in the pre- and mid-treatment setting using expert primary gross tumour volume (GTV) and clinical target volume (CTV) delineations in locoregionally advanced head-and-neck squamous cell carcinoma (HNSCC) and (non-)small cell lung cancer [(N)SCLC]. Material and methods: Five and six observers participated in the HNSCC and (N)SCLC arm, respectively, and provided delineations for five cases each. Imaging data consisted of CT studies partly complemented by FDG-PET and was provided in two separate phases for pre- and mid-treatment. Global delineation compatibility was assessed with a volume overlap metric (the Generalised Conformity Index), while local extremes of IOV were identified through the standard deviation of surface distances from observer delineations to a median consensus delineation. Details of delineation procedures, in particular, GTV to CTV expansion and adaptation strategies, were collected through a questionnaire. Results: Volume overlap analysis revealed a worsening of IOV in all but one case per disease site, which failed to reach significance in this small sample (p-value range .063-.125). Changes in agreement were propagated from GTV to CTV delineations, but correlation could not be formally demonstrated. Surface distance based analysis identified longitudinal target extent as a pervasive source of disagreement for HNSCC. High variability in (N)SCLC was often associated with tumours abutting consolidated lung tissue or potentially invading the mediastinum. Adaptation practices were variable between observers with fewer than half stating that they consistently adapted pre-treatment delineations during treatment. Conclusion: IOV in target volume delineation increases during treatment, where a disparity in institutional adaptation practices adds to the conventional causes of IOV. Consensus guidelines are urgently needed.

Background and purpose Early radiation-induced esophageal toxicity (RIET) is one of the major side effects in patients with non-small cell lung cancer (NSCLC) and can be a reason for treatment interruptions. As the age of patients with NSCLC and corresponding comorbidities continue to increase, primary radiotherapy alone is a commonly used alternative treatment in these cases. The aim of the present study is to compare dosimetric and clinical parameters from the previously reported CHARTWEL trial for their ability to predict esophagitis and investigate potential differences in the accelerated and conventional fractionation arm. Material and methods 146 patients of the Dresden cohort of the randomized phase III CHARTWEL trial were included in this post-hoc analysis. Side effects were prospectively scored weekly during the first 8 weeks from start of radiotherapy. To compare both treatment arms, recorded dose–volume parameters were adjusted for the different fractionation schedules. Logistic regression was performed to predict early RIET for the entire study group as well as for the individual treatment arms. Different dosimetric and clinical parameters were tested. Results Patients receiving the accelerated CHARTWEL schedule experienced earlier and more severe esophagitis (e.g. 20.5% vs. 9.6% ≥grade 2 at week 3, respectively). In contrast, the median time period for recovery of grade 1 esophagitis was significantly longer for patients with conventional fractionation compared to the CHARTWEL group (median [range]: 21 [12–49] days vs. 15 [7–84] days, p = 0.028). In univariable logistic regression none of the dose–volume parameters showed a significant correlation with early RIET grade ≥ 2 in the conventional irradiation group. In contrast, for patients receiving CHARTWEL, the physical dose–volumes parameters V40 and V50; and re-scaled values VEQD2,50 and VEQD2,60 were significant predictors of early RIET grade ≥ 2. Dose–volume parameters remained different between CHARTWEL and conventional fractionation even after biological rescaling. Conclusion Our results show a more dominant dose-volume effect in the CHARTWEL arm compared to conventional fractionation, especially for higher esophageal doses. These findings support the notion that dose–volume parameters for radiation esophagitis determined in a specific and time dependent setting of field arrangements can not be easily transferred to another setting. In clinical practice esophageal volumes receiving 40 Gy or more should be strictly limited in hyperfractionated-accelerated fraction schemes.

Background and purpose Standard treatment of high grade gliomas includes gross tumour resection followed by radio(chemo)therapy. Radiotherapy inevitably leads to irradiation of normal brain tissue. The goal of this prospective, longitudinal study was to use MRI to quantify normal appearing white and grey matter changes following radiation treatment as a function of dose and time after radiotherapy. Materials and methods Pre-radiotherapy (proton or photon therapy) MRI and follow-up MRIs collected in 3 monthly intervals thereafter were analysed for 22 glioma patients and included diffusion tensor imaging, quantitative T1, T2* and proton density mapping. Abnormal tissue was excluded from analysis. MR signal changes were quantified within different dose bin regions for grey and white matter and subsequently for whole brain white matter. Results We found significant reductions in mean diffusivity, radial diffusivity, axial diffusivity and T2* in normal appearing white matter regions receiving a radiation dose as low as 10–20 Gy within the observational period of up to 18 months. The magnitude of these changes increased with the received radiation dose and progressed with time after radiotherapy. Whole brain white matter also showed a significant reduction in radial diffusivity as a function of radiation dose and time after radiotherapy. No significant changes were observed in grey matter. Conclusion Diffusion tensor imaging and T2* imaging revealed normal appearing white matter changes following radiation treatment. The changes were dose dependant and progressed over time. Further work is needed to understand the underlying tissue changes and to correlate the observed diffusion changes with late brain malfunctions.

Retrospective evaluation of serial FDG-PET/CT scans in head and neck squamous cell cancer (HNSCC) patient's follow-up after primary radiochemotherapy (RCTx), to assess the diagnostic accuracy of an experienced observer vs. an objective classification compared to standard clinical follow-up examinations.Sixty-nine patients with locally advanced HNSCC were included, who received curative RCTx. Follow-up included serial FDG-PET/CT at the following time intervals t1: ≤ 270 d, t2: 271-540 d, t3: 540 d after curative RCTx. The likelihood to detect local recurrences, nodal and distant metastases were compared between (i) experienced observer, (ii) an objective classification system by Zundel et al. 25, and (iii) routine clinical follow-up examinations.Twenty-two local recurrences, 7 nodal and 17 distant metastases were recorded during the follow-up. The diagnostic accuracy for local recurrence of the experienced observer vs. objective classification was 78 % vs. 77 % for t1, 83 % vs. 79 % for t2 and 100 % vs. 84 % for t3.The classification (ii) and the conventional follow-up (iii) resulted in a relatively high amount of equivocal findings reducing the diagnostic accuracy.Evaluation of FDG-PET/CT by an experienced observer in follow-up of HNSCC patients after curative RCTx resulted in the highest diagnostic accuracy in comparison to an objective classification and to routine clinical examination.HNSCC is a malignant tumor with a high likelihood of recurrence, especially in the first two years after curative RCTx. Early detection of recurrence is of high clinical importance, since there are several effective second line therapies that may have curative potential in some patients.ZIEL: Retrospektive Analyse der FDG-PET/CT in der Nachsorge von Patienten mit primär radiochemotherapierten zervikalen Plattenepithelkarzinomen (HNSCC). Vergleich der diagnostischen Genauigkeit des erfahrenen Befunders mit einem objektiven Klassifizierungssystem und mit der klinischen Nachsorgeuntersuchung.69 Patienten, die wegen eines lokal fortgeschrittenen HNSCC eine kurative Radiochemotherapie (RCTx) erhielten, wurden eingeschlossen. Die Nachsorge umfasste serielle FDG-PET/CT nach RCTx zu folgenden Zeitintervallen t1: ≤ 270 d, t2: 271–540 d, t3: 540 d. Die Detektionsraten von Lokalrezidiven, Lymphknoten- und Fernmetastasen durch den erfahrenen Befunder (i), das objektive Klassifikationsverfahren (ii) nach Zundel 25 sowie durch die routinemäßige klinische Nachsorge (iii) wurden verglichen.Insgesamt wurden 22 Patienten mit Lokalrezidiven, 7 mit Lymphknoten-, und 17 mit Fernmetastasen detektiert. Die diagnostischen Genauigkeiten des erfahrenen Untersuchers (i) und des objektiven Klassifizierungssystems (ii) bezüglich der Lokalrezidive betrugen 78 % und 77 % zu t1, 83 % bzw. 79 % zu t2 und 100 % bzw. 84 % zu t3. Das Klassifizierungssystem nach Zundel, aber auch die konventionelle Nachsorgeuntersuchung führte zu einem relativ hohen Anteil uneindeutiger Befunde, was sich negativ auf die diagnostische Genauigkeit auswirkte.Die Auswertung der FDG-PET/CT bei Patienten mit lokal fortgeschrittenen HNSCC nach kurativer RCTx durch den erfahrenen Befunder hat die höchste diagnostische Genauigkeit für die Detektion von Lokalrezidiven und/oder Metastasen im Vergleich zu einem objektiven Klassifizierungssystem und der routinemäßigen klinischen Nachsorge.Vor dem Hintergrund zahlreicher effektiver Zweitlinientherapien mit teils kurativem Potenzial und der hohen Rezidivneigung in den ersten beiden Jahren nach Primärtherapie ist die frühzeitige und exakte Detektion von Rezidiven und Metastasen bei HNSCC-Patienten von großer Bedeutung.

Highlights • Tumour volume, p16 status and N stage could be validated regarding LRC and OS. • Addition of cancer stem cell markers can further improve the baseline model. • Prognostic value of tumour hypoxia warrants analysis in a larger cohort., Objective To independently validate the impact of tumour volume, p16 status, cancer stem cell (CSC) marker expression and hypoxia-associated gene signatures as potential prognostic biomarkers for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), who underwent primary radiotherapy or radiochemotherapy (RCTx). These markers have previously been reported in a study of the German Cancer Consortium Radiation Oncology Group (DKTK-ROG) (Linge et al., 2016). Materials and methods In this retrospective monocentric study, 92 patients with locally advanced HNSCC were included. Univariable and multivariable logistic regressions and Cox models presented in the study of the DKTK-ROG were validated using the area under the curve (AUC) and the concordance index (ci), respectively. The primary endpoint of this study was loco-regional tumour control (LRC) after primary RCTx. Results Although both cohorts significantly differed in the proportion of the tumour subsites, the parameters tumour volume, p16 status and N stage could be validated regarding LRC and overall survival (OS) using multivariable Cox regression (LRC ci: 0.59, OS ci: 0.63). These models were slightly improved by combination with the putative CSC marker CD44 (LRC ci: 0.61, OS ci: 0.69). The logistic regression model for 2-year LRC based on tumour volume, p16 status and CD44 protein was validated with an AUC of 0.64. The patient stratification based on hypoxia-associated gene signatures status was similar to the original study but without significant differences in LRC and OS. Conclusions In this validation study, the inclusion of the putative CSC marker CD44 slightly improved the prognostic performance of the baseline parameters tumour volume, p16 status and N stage. No improvement was observed when including expressions of the hypoxia-associated gene signatures. Prospective validation on a larger cohort is warranted to assess the clinical relevance of these markers.

Purpose: The aim of this study was to identify and independently validate a novel gene signature predicting locoregional tumor control (LRC) for treatment individualization of patients with locally advanced HPV-negative head and neck squamous cell carcinomas (HNSCC) who are treated with postoperative radio(chemo)therapy (PORT-C). Experimental Design: Gene expression analyses were performed using NanoString technology on a multicenter training cohort of 130 patients and an independent validation cohort of 121 patients. The analyzed gene set was composed of genes with a previously reported association with radio(chemo)sensitivity or resistance to radio(chemo)therapy. Gene selection and model building were performed comparing several machine-learning algorithms. Results: We identified a 7-gene signature consisting of the three individual genes HILPDA, CD24, TCF3, and one metagene combining the highly correlated genes SERPINE1, INHBA, P4HA2, and ACTN1. The 7-gene signature was used, in combination with clinical parameters, to fit a multivariable Cox model to the training data (concordance index, ci = 0.82), which was successfully validated (ci = 0.71). The signature showed improved performance compared with clinical parameters alone (ci = 0.66) and with a previously published model including hypoxia-associated genes and cancer stem cell markers (ci = 0.65). It was used to stratify patients into groups with low and high risk of recurrence, leading to significant differences in LRC in training and validation (P < 0.001). Conclusions: We have identified and validated the first hypothesis-based gene signature for HPV-negative HNSCC treated by PORT-C including genes related to several radiobiological aspects. A prospective validation is planned in an ongoing prospective clinical trial before potential application in clinical trials for patient stratification. Clin Cancer Res; 24(6); 1364–74. ©2018 AACR.

To compare 4 different proton pencil beam scanning (PBS) treatment approaches for unilateral head and neck cancer (HNC) targets in terms of robustness, including anatomical changes during the treatment course.

Background In early-stage non-small cell lung cancer (NSCLC) without affected lymph nodes detected at staging, surgical resection is still the mainstay of treatment. However, in patients with metastatic mediastinal lymph nodes (pN2) or non-radically resected primary tumors (R1/R2), postoperative radiotherapy (possibly combined with chemotherapy) is indicated. So far, investigations about time factors affecting postoperative radiotherapy have only examined the waiting time defined as interval between surgery and start of radiotherapy, but not the overall treatment time (OTT) itself. Conversely, results from trials on primary radio(chemo)therapy in NSCLC show that longer OTT correlates with significantly worse local tumor control and overall survival rates. This time factor of primary radio(chemo)therapy is thought to mainly be based on repopulation of surviving tumor cells between irradiation fractions. It remains to be elucidated if such an effect also occurs when patients with NSCLC are treated with postoperative radiotherapy after surgery (and chemotherapy). Our own retrospective data suggest an advantage of shorter OTT also for postoperative radiotherapy in this patient group. Methods/design This is a multicenter, prospective randomized trial investigating whether an accelerated course of postoperative radiotherapy with photons or protons (7 fractions per week, 2 Gy fractions) improves locoregional tumor control in NSCLC patients in comparison to conventional fractionation (5 fractions per week, 2 Gy fractions). Target volumes and total radiation doses will be stratified in both treatment arms based on individual risk factors. Discussion For the primary endpoint of the study we postulate an increase in local tumor control from 70% to 85% after 36 months. Secondary endpoints are overall survival of patients; local recurrence-free and distant metastases-free survival after 36 months; acute and late toxicity and quality of life for both treatment methods. Trial registration ClinicalTrials.gov, NCT02189967. Registered on 22 May 2014. Electronic supplementary material The online version of this article (doi:10.1186/s13063-017-2346-0) contains supplementary material, which is available to authorized users.

Background. Tumour hypoxia can be measured by FMISO-PET and negatively impacts local tumour control in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The aim of this post hoc analysis of a prospective clinical trial was to investigate the spatial variability of FMISO hypoxic subvolumes during radio-chemotherapy and the co-localisation of these volumes with later recurrences as a basis for individualised dose prescription trials with dose escalation defined by FMISO-PET. Methods. Sequential FMISO scans of 12 (of 25) patients presenting residual hypoxia taken before (FMISOpre) and during (FMISOw1–FMISOw5) radio-chemotherapy were analysed regarding the stability of the FMISO subvolumes and, in case of local failure, their correlation to local relapse. Results. Consecutive FMISO-PET positive volumes could be classified as moderately stable with Dice conformity indices of 62% and 58% up to the second week of treatment. Substantial volumetric variation during treatment was observed, with more than 20% geographic miss in all patients and more than 40% in half of the patients. The localisation of the maximum standardised uptake value (SUVmax) differed with a mean distance of 7.0 mm and 13.5 mm between the pre-therapeutic and first or second FMISO-PET during treatment. A stable hypoxic consensual volume (i.e. overlap of pre-therapeutic FMISO and intra-treatment FMISO subvolumes up to week two, generated by different contouring methods) was determined for six patients with imaging information of local recurrence. Three of these six local recurrences were located within this consensual volume. Conclusions. Our data suggest that selective dose painting to hypoxic tumour subvolumes requires adaptation during treatment and sufficient margins. An alternative strategy is to escalate the dose to the gross tumour volume, accepting lesser escalation of dose outside hypoxic areas if indicated by constraints for organs at risk.

Highlights • Most recurrences occurred within the primary tumor or initially affected lymph nodes. • All sites of loco-regional recurrence had received 92–106% of the prescribed dose. • No isolated nodal failure occurred, supporting the use of selective nodal irradiation., Objectives Concurrent radiochemotherapy (RCHT) is standard treatment in locally advanced small cell lung cancer (SCLC) patients. Due to conflicting results on elective nodal irradiation (ENI) or selective node irradiation (SNI) there is no clear evidence on optimal target volumes. Therefore, the purposes of this study were to assess the sites of recurrent disease in SCLC and to evaluate the feasibility of SNI versus ENI. Methods A retrospective single-institution study of 43 consecutive patients treated with RCHT was performed. After state-of-the-art staging including FDG-PET/CT, all patients underwent three-dimensional conformal radiotherapy to a total dose of 45 Gy in twice-daily fractions of 1.5 Gy starting concurrently with the first or second chemotherapy cycle. All sites of loco-regional recurrences were correlated to the initial tumor and dose delivered. The impact of potential prognostic variables on outcome was evaluated using the Cox-regression model. Results 13 patients (30%) relapsed locally or regionally: six within the initial primary tumor volume, five within the initially affected lymph nodes, one metachronously within primary tumor and initially affected lymph nodes, and one both inside and outside of the initial nodal disease. All sites of loco-regional recurrence had received 92–106% of the prescribed dose. Conclusion In our study most recurrences occurred within the primary tumor or initially affected lymph nodes, or distantly. We did not register any case of isolated nodal failure, supporting the use of selective nodal irradiation, possibly with the addition of supraclavicular irradiation in patients with nodal disease in the upper mediastinum.

The purpose of this work is to analyze patterns of care and outcome after stereotactic body radiotherapy (SBRT) for centrally located, early-stage, non-small cell lung cancer (NSCLC) and to address the question of potential risk for increased toxicity in this entity.A total of 90 patients with centrally located NSCLC were identified among 613 cases in a database of 13 German and Austrian academic radiotherapy centers. The outcome of centrally located NSCLC was compared to that of cases with peripheral tumor location from the same database.Patients with central tumors most commonly presented with UICC stage IB (50 %), while the majority of peripheral lesions were stage IA (56 %). Average tumor diameters were 3.3 cm (central) and 2.8 cm (peripheral). Staging PET/CT was available for 73 and 74 % of peripheral and central tumors, respectively. Biopsy was performed in 84 % (peripheral) and 88 % (central) of cases. Doses varied significantly between central and peripheral lesions with a median BED10 of 72 Gy and 84 Gy, respectively (p 0.001). Fractionation differed as well with medians of 5 (central) and 3 (peripheral) fractions (p 0.001). In the Kaplan-Meier analysis, 3-year actuarial overall survival was 29 % (central) and 51 % (peripheral; p = 0.004) and freedom from local progression was 52 % (central) and 84 % (peripheral; p 0.001). Toxicity after treatment of central tumors was low with no grade III/IV and one grade V event. Mortality rates were 0 and 1 % after 30 and 60 days, respectively.Local tumor control in patients treated with SBRT for centrally located, early-stage NSCLC was favorable, provided ablative radiation doses were prescribed. This was, however, not the case in the majority of patients, possibly due to concerns about treatment-related toxicity. Reported toxicity was low, but prospective trials are needed to resolve the existing uncertainties and to establish safe high-dose regimens for this cohort of patients.

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 per- formed 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 technolo- gies and escalated irradiation doses was observed, but patient char- acteristics (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 progres- sion (FFLP) and overall survival (OS) were 79.6% and 47.1%, respec- tively. 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 consider- able interinstitutional variability and time trends in SBRT practice. Radiotherapy dose was identified as a major treatment factor influ- encing local tumor control and OS.

BACKGROUND AND PURPOSE: Reliable tumor staging is a fundamental pre-requisite for efficient tumor therapy and further prognosis. The aim of this study was to compare head and neck cancer (HNC) staging before and after FDG-PET/CT, evaluating the stage modifications for radiotherapy (RT) planning. PATIENTS AND METHODS: A total of 102 patients with untreated primary HNC, who underwent conventional staging and staging including FDG-PET/CT before RT, were enrolled in this retrospective study. Blinded pre-FDG-PET/CT and post-FDG-PET/CT staging data were compared. The impact on patient management was tested by comparing the intention before and after FDG-PET/CT. RESULTS: Significant modifications of T, N, and M stage as well as clinical stage were detected after inclusion of FDG-PET/CT data (p = 0.002, 0.0006, 0.001, 0.03, respectively). Overall, the implementation of FDG-PET/CT led to modification of RT intention decision in 14 patients. CONCLUSIONS: FDG-PET/CT demonstrates essential influence on tumor staging in HNC patients scheduled for irradiation. Implementation of FDG-PET/CT in imaging protocol improves selection of candidates for curative and palliative RT and allows further optimization of treatment management and therapy intention.

Background Primary radiochemotherapy with photons is the standard treatment for locally advanced-stage non-small cell lung cancer (NSCLC) patients. Acute radiation-induced side effects such as oesophagitis and radiation pneumonitis limit patients’ quality of life, and the latter can be potentially life-threatening. Due to its distinct physical characteristics, proton therapy enables better sparing of normal tissues, which is supposed to translate into a reduction of radiation-induced side effects. Methods/design This is a single-centre, prospective, randomised controlled, phase II clinical trial to compare photon to proton radiotherapy up to 66 Gy (RBE) with concomitant standard chemotherapy in patients with locally advanced-stage NSCLC. Patients will be allocated in a 1:1 ratio to photon or proton therapy, and treatment will be delivered slightly accelerated with six fractions of 2 Gy (RBE) per week. Discussion The overall aim of the study is to show a decrease of early and intermediate radiation-induced toxicity using proton therapy. For the primary endpoint of the study we postulate a decrease of radiation-induced side effects (oesophagitis and pneumonitis grade II or higher) from 39 to 12%. Secondary endpoints are locoregional and distant failure, overall survival and late side effects. Trial registration Registered at ClinicalTrials.gov with Identifier NCT02731001 on 1 April 2016. Electronic supplementary material The online version of this article (doi:10.1186/s13063-016-1679-4) contains supplementary material, which is available to authorized users.

Purpose: To explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer. Patients and methods: Twenty-five patients with stage III/IV head and neck cancer were investigated with [18F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8–10 Gy, 18–20 Gy,50–60 Gy). FMISO PET/CT image parameters were extracted including maximumtumour-to-background (TBRmax) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests. Results: FMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023–0.048 and 0.042–0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS. Conclusion: This prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going.

Background: Recently published data show some controversy concerning the impact of [18F]-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) in predicting head and neck tumors (HNT) outcome. Assessment of tumor blood supply parameters using dynamic contrast-enhanced CT (DCE-CT) may deliver additional information concerning this important question. Purpose: To evaluate the contribution of DCE-CT implemented in pretherapeutic FDG-PET/CT protocol for prognosis prediction in patients with HNT. Material and Methods: Ten consecutive patients (median age 50 years, range 47–74 years) with histologically proven HNT underwent FDG-PET/CT with DCE-CT before treatment. FDG uptake was measured by maximum standardized uptake value (SUVmax). Relative tumor blood volume (rTBV) was determined from DCE-CT using Patlak analysis. Intratumoral heterogeneity was assessed by means of lacunarity analysis. Obtained values were compared with time-to-progression and overall survival. PET and DCE-CT images were compared on a pixel-by-pixel basis using Pearson coefficient of correlation. Results: Three patients with lower FDG uptake (SUVmax: 8±1) and five patients with higher FDG uptake (SUVmax: 15±4, P=0.004) were free of local recurrence for 24 months. Two groups of patients with significantly differing lower (group A: 0.37±0.02, n=6) and higher (group B: 0.52±0.01, n=4; P2=0.1). Conclusion: FDG-PET/CT and DCT-CT are complementary methods for surveillance assessment in patients with HNT. Implementation of DCE-CT in the pretreatment FDG-PET/CT protocol may improve tumor outcome prediction.

To assess possible consequences for radiotherapy (RT) planning, e.g., reduction of treatment volume by a decreased tumour volume in Fluor-18-fluoro-deoxy-glucose-Positron emission tomography (FDG-PET) based on a close-meshed evaluation of FDG uptake in primary head and neck cancer (HNC) during RT.PET data were analysed using a source-to-background based algorithm. The following parameters were obtained: max. standardised uptake value (SUVmax), PET-based gross tumour volume (GTV-PET) and metabolic volume (MV).While the median SUVmax decreased (initial: 15.2, 1st/2nd week: 10.2, 3rd/4th week: 6.5, 5th/6th week: 6.4), the median values of GTV-PET (9.3 cm(3), 12.4 cm(3), 14.0 cm(3), 17.9 cm(3)) and MV (92.2 cm(3), 61.7 cm(3), 60.0 cm(3), 71.3 cm(3)) seemed to increase during radiotherapy. The intra-individual development of SUVmax could be divided into two groups: group A having continuously decreasing values of SUVmax (n = 10 patients), and group B having a temporary increase of SUVmax (n = 13).Data suggest that a reduction of treatment volume is not possible by an adaptive re-planning based on FDG-PET, e.g., at 50 Gy. This may be caused by a consecutive therapy associated inflammation. This limitation is probably related to the use of a source-to-background based algorithm.

Background and purpose Loco-regional failure after radiotherapy with total doses of 60–70 Gy for non-small cell lung cancer (NSCLC) remains a major clinical problem. Escalation of radiation dose is often limited because of exceeding normal tissue constraints. The present study was designed to test the hypothesis that a reduction in disease volume during radiotherapy detected by FDG PET/CT would facilitate radiation dose escalation, whilst remaining within normal tissue constraints. Materials and methods Ten patients with localised inoperable NSCLC were prospectively enrolled. Each received standard 3D-conformally planned radiotherapy to a dose of 66 Gy in 33 fractions over 6.5 weeks. FDG PET/CT imaging in the treatment position was performed prior to treatment and repeated following 50 or 60 Gy. CT and PET-delineated gross tumour volumes were generated and a composite created. A margin of 15mm was added in all planes to form the planning target volume (PTV). Treatment planning was performed to compare two dose escalation strategies: 78 Gy delivered to the initial PTV with treatment in two phases (shrinking field), i.e., 66 Gy to the initial PTV with a 12 Gy-boost to the PTV after 50/60 Gy. As an alternative planning approach the maximal dose without exceeding normal tissue constraints was evaluated for each patient (individualized dose prescription). Results There was a median PTV reduction after 50/60 Gy of 20%. Delivering 78 Gy to the initial PTV could have been achieved in 4/10 patients. Of the remaining 6, delivering 78 Gy to the initial PTV would have exceeded normal tissue constraints and no benefit was seen when delivered in two phases. The results from the individualized dose prescription indicated a higher median maximal dose when treatment would be given in two phases compared to one phase resulting in a modest increase of calculated tumour control probability. Conclusions Our data suggest that despite tumour shrinkage determined by subsequent FDG PET/CT during treatment the tested adaptive targeting strategy would result only in a modest improvement in the context of dose escalation. Further studies on the optimal use of FDG PET/CT and other approaches for dose escalation in loco-regionally advanced NSCLC are warranted.

PET / CT with FDG and contrast medium is used in planning, monitoring and follow-up in patients with head and neck cancer. The aim of this article is to demonstrate the current role of PET / CT for patients with head and neck cancer undergoing a primary curative radiotherapy.

The purpose of this work was to prove the validity of the mean lung dose (MLD), widely used in clinical practice to estimate the lung toxicity of a treatment plan, by reevaluating experimental data from mini pigs. A total of 43 mini pigs were irradiated in one of four dose groups (25, 29, 33, and 37 Gy). Two regimens were applied: homogeneous irradiation of the right lung or partial irradiation of both lungs—including parts with lower dose—but with similar mean lung doses. The animals were treated with five fractions with a linear accelerator applying a CT-based treatment plan. The clinical lung reaction (breathing frequency) and morphological changes in CT scans were examined frequently during the 48 weeks after irradiation. A clear dose–effect relationship was found for both regimens of the trial. However, a straightforward relationship between the MLD and the relative number of responders with respect to different grades of increased breathing frequency for both regimens was not found. A morphologically based parameter NTCPlung was found to be more suitable for this purpose. The dependence of this parameter on the MLD is markedly different for the two regimens. In clinical practice, the MLD can be used to predict lung toxicity of a treatment plan, except for dose values that could lead to severe side effects. In the latter mentioned case, limitations to the predictive value of the MLD are possible. Such severe developments of a radiation-induced pneumopathy are better predicted by the NTCPlung formalism. The predictive advantage of this parameter compared to the MLD seems to remain in the evaluation and comparison of widely differing dose distributions, like in the investigated trial.

For the case of pharyngeal carcinomas, the clinical value as well as the stability of several evaluation methods of MR tomographic perfusion measurement are compared. Eighteen patients suffering from histologically proven squamous cell carcinomas were investigated by MR tomography (1.5 T, 0.2 mmol/kg Gd‐DTPA) prior to and during radiation therapy. Perfusion measurements were performed using a double‐echo FLASH sequence. Parameters describing regional blood flow, blood volume, mean transit time, and interstitial concentration of contrast medium (CM) were calculated, applying seven different combinations of correction approaches (separating the shortening of T1 and T2∗, arterial input function (AIF), and tumor shunts). Their correlations to MR independent tumor physiological parameters were analyzed (metabolic activity measurements using 18F‐FDG‐PET, polarographical pO2 measurement, tumor volume). Significant improvements of the correlation between perfusion‐dependent and other tumor physiological parameters could be achieved by decoupling the shortening of T1 and T2∗ and by applying of the tumor shunt model. Deconvolution from the AIF deteriorated the correlation. Therefore, the elimination of the T1 shortening due to interstitial CM proves to be essential for MR perfusion measurements on contrast medium uptaking lesions. Depending on the measurement conditions (temporal resolution, signal‐to‐noise ratio), the consideration of the AIF can even make the results significantly worse by introducing additional measuring errors. PACS numbers: 87.61.‐c

PO-0616: HPV, CSC marker expression and tumor hypoxia as prognosticators for LRC in patients with HNSCC

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.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.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.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.

At present, radiotherapy alone or in combination with chemotherapy offers the only chance of cure of medically inoperable or locally advanced unresectable non-small cell lung cancer. The radiobiological basis and clinical results of current dose and fractionation concepts in the primary radiotherapy of NSCLC are briefly reviewed. Whenever possible, focus is given to the results of randomized phase III trials. With the exception of early disease treated to doses higher than 60 Gy, the prognosis of inoperable localized NSCLC is very poor. Local recurrence is the major cause of failure after radiation therapy calling for intensified local treatment. Dose-escalation using conventional fractionation or moderate hypofractionation is promising but randomized trials are presently not available. Dose-escalated hyperfractionation theoretically offers advantages, however, there appears currently no strong evidence from randomized trials supporting this approach in NSCLC. The highly accelerated CHART regimen significantly improved survival by 9% compared to standard radiotherapy. Nevertheless, even when treated with CHART, about 80% of all patients will eventually develop local recurrence and 60% distant metastases. Many trials on combined radiochemotherapy have used radiotherapy regimens that are not optimal from a current perspective. Because of the high rate of both, local recurrence and distant metastases, future research should be directed to further intensify radiotherapy as well as to integrate such protocols with systemic treatment in carefully selected patients. Since toxicity is expected to increase, state-of-the-art 3D conformal radiation techniques need to be part of clinical trials testing such strategies.

Milestones during the past decades for improving radiotherapy of lung cancer include identification of clinical prognostic parameters for stratification and individualized prescription, better anatomical visualisation of the tumour and regional lymph nodes, improved definition of the target volume, improved dosimetry, CT-based treatment planning with adequate algorithms, verification of treatment application by in-room imaging, optimization of total dose, dose per fraction, and overall treatment time, identification of dose-volume constraints for normal tissues, and integration of radiotherapy with chemotherapy [1–4]. Without doubt these achievements have led to improved loco-regional tumour control, reduced normal tissue toxicity and better survival in a host of clinical trials and, much less well investigated, possibly also in the overall population of patients treated for this disease. However, it is equally true that this progress has been only moderate and that both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) continue to have a grim prognosis if not detected at a very early stage of disease. A widely spread perception is that distant metastases is by far the leading obstacle in this disease and that therefore intensification of the systemic treatment is the sole logical strategy to improve outcome. Without question distant metastases do occur in a large proportion of patients with lung cancer. Nevertheless it is of key importance to realize that also local recurrence rates are extremely high in locally advanced lung cancers treated by radio- and radiochemotherapy. Careful follow-up studies in NSCLC after radiation doses >60Gy have reported loco-regional failure rates within the first few years up to 80–90% which often even exceeds the rates of distant metastases in these cohorts [5]. A narrow view merely on the high distant metastasis rates has led to a host of pragmatic trials which apply standard radiotherapy and compare chemotherapy schedules A with B, without any effort to optimize loco-regional treatment. Because of the high loco-regional recurrence rates it appears very unlikely that this approach will lead to major further improvements of overall outcome of therapy in lung cancer even if more potent anti-metastatic compounds will be developed. This point of view is supported by recent large randomized trials and meta-analysis showing that adjuvant chemotherapy after curative surgery in stage I–III (in many cases followed by postoperative radiotherapy) decreases the distant metastases rates and increases the 5-year survival by approximately 5% [6]. This has led to the implementation of adjuvant chemotherapy in this setting as a standard of care. However in the context of radiochemotherapy the impact of a decrease in distant metastases by 5–10% on overall survival would be extremely difficult to detect given the high local recurrence rates. This is in line with the experience that improved survival by introducing or optimizing chemotherapy in the context of radiotherapy of lung cancer was often caused by improved locoregional control and not by decreased metastases [7,8].

Patienten mit einem fortgeschrittenen, inoperablen nichtkleinzelligen Bronchialkarzinom im Stadium III, bei denen eine kurative Therapie bis 60 Gy nicht durchgefuhrt werden konnte, wurden in der Klinik und Poliklinik fur Strahlentherapie und Radioonkologie der Universitatsklinik Dresden mit 25 Gy in funf Fraktionen uber ein bis zwei Wochen behandelt. Die Uberlebensrate der so behandelten Patienten wurde in dieser retrospektiven Untersuchung mit den Ergebnissen der im gleichen Zeitraum kurativ behandelten Patienten verglichen. 298 Patienten mit einem histologisch oder zytologisch gesicherten nichtkleinzelligen Bronchialkarzinom im Stadium III wurden zwischen 1985 und 1994 mit 60 Gy in 30 Fraktionen (n = 80), 40 Gy in 20 Fraktionen (n = 26) oder 25 Gy in funf Fraktionen (n = 192) primar strahlentherapeutisch behandelt. Das Uberleben der Patienten nach Therapiebeginn wurde aktuarisch ausgewertet. Prognosefaktoren wurden mit uni- und multivariaten Methoden getestet. Die mediane Uberlebenszeit betrug fur alle Patienten sechs Monate (95%-Vertrauensbereich 5; 7). Die Ergebnisse der Strahlentherapie bis 60 Gy, 40 Gy und 25 Gy waren signifikant voneinander unterschiedlich, die medianen Uberlebenszeiten betrugen elf Monate (9; 13), sechs Monate (4; 8) und funf Monate (4; 6). In der multivariaten Analyse verlor das Behandlungsschema seinen signifikanten Einflus auf das Uberleben. Der wichtigste prognostische Parameter war der Allgemeinzustand der Patienten. Bei Berucksichtigung des Allgemeinzustands als wichtigstem Prognosekriterium war in unserem Patientenkollektiv die Uberlebenszeit nach hypofraktionierter Bestrahlung mit 25 Gy nicht signifikant schlechter als nach konventioneller Fraktionierung bis 60 Gy. Hypofraktionierte Schemata binden die Patienten nur kurzzeitig an ein strahlentherapeutisches Zentrum, sind okonomisch gunstig und haben in anderen Studien eine gute symptomatische Wirkung belegt. Bei unzweifelhaft palliativer Indikation erscheint uns daher die Behandlung mit 25 Gy in funf Fraktionen uber ein bis zwei Wochen oder ein vergleichbares hypofraktioniertes Schema als sinnvolles Therapieangebot. Patients with advanced Stage III inoperable non-small cell lung cancer who were not suitable for irradiation with curative doses, were treated at the Department of Radiotherapy of the University Hospital of Dresden with 25 Gy in 5 fractions over 1 to 2 weeks. Survival of these patients was compared in this retrospective study to the survival of patients treated during the same period with 60 Gy in 30 fractions. Between 1985 and 1994 298 patients were treated for a histologically or cytologically proven non-small cell lung carcinoma with 60 Gy in 30 fractions (n = 80), with 40 Gy in 20 fractions (n = 26) or with 25 Gy in 5 fractions (n = 192). Overall survival was determined using actuarial methods. Prognostic parameters were analyzed using uni- and multivariate tests. Median overall survival for all patients was 6 months (95% confidence interval 5; 7). In univariate analysis, survival of the patients treated with 60 Gy was significantly better than survival in the other groups. Median survival was 11 months (9; 13) after 60 Gy, 6 months (4; 8) after 40 Gy and 5 months (4; 6) after 25 Gy. In multivariate analysis the treatment schedule lost its significant influence on outcome of the therapy. The most important prognostic parameter was the performance status of the patients. When stratified for performance status as the most important prognostic parameter the survival time after hypofractionated irradiation to 25 Gy given in 5 fractions in 1 to 2 weeks was not significantly different from the results after conventional fractionation to 60 Gy. Hypofractionated radiation schedules are often more convenient for the patient, economical, and have been shown to be effective in symptom control. Thus, in clear palliative situations hypofractionated treatment with 25 Gy in 5 fractions or a comparable schedule appears to be a reasonable therapeutic option.