Search

(1) Background: Patients with locally advanced head and neck squamous cell carcinoma (HNSCC) who are biologically at high risk for the development of loco–regional recurrences after postoperative radiotherapy (PORT) but at intermediate risk according to clinical risk factors may benefit from additional concurrent chemotherapy. In this matched-pair study, we aimed to identify a corresponding predictive gene signature. (2) Methods: Gene expression analysis was performed on a multicenter retrospective cohort of 221 patients that were treated with postoperative radiochemotherapy (PORT-C) and 283 patients who were treated with PORT alone. Propensity score analysis was used to identify matched patient pairs from both cohorts. From differential gene expression analysis and Cox regression, a predictive gene signature was identified. (3) Results: 108 matched patient pairs were selected. We identified a 2-metagene signature that stratified patients into risk groups in both cohorts. The comparison of the high-risk patients between the two types of treatment showed higher loco–regional control (LRC) after treatment with PORT-C (p < 0.001), which was confirmed by a significant interaction term in Cox regression (p = 0.027), i.e., the 2-metagene signature was indicative for the type of treatment. (4) Conclusion: We have identified a novel gene signature that may be helpful to identify patients with high-risk HNSCC amongst those at intermediate clinical risk treated with PORT, who may benefit from additional concurrent chemotherapy.

Biomarkers with relevance for loco-regional therapy are needed in human papillomavirus negative aka HPV(-) head and neck squamous cell carcinoma (HNSCC). Based on the premise that DNA methylation pattern is highly conserved, we sought to develop a reliable and robust methylome-based classifier identifying HPV(-) HNSCC patients at risk for loco-regional recurrence (LR) and all-event progression after postoperative radiochemotherapy (PORT-C). The training cohort consisted of HPV-DNA negative HNSCC patients (n = 128) homogeneously treated with PORT-C in frame of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG) multicenter biomarker trial. DNA Methylation analysis was performed using Illumina 450 K and 850 K-EPIC microarray technology. The performance of the classifier was integrated with a series of biomarkers studied in the training set namely hypoxia-, 5-microRNA (5-miR), stem-cell gene-expression signatures and immunohistochemistry (IHC)-based immunological characterization of tumors (CD3/CD8/PD-L1/PD1). Validation occurred in an independent cohort of HPV(-) HNSCC patients, pooled from two German centers (n = 125). We identified a 38-methylation probe-based HPV(-) Independent Classifier of disease Recurrence (HICR) with high prognostic value for LR, distant metastasis and overall survival (P < 10-9 ). HICR remained significant after multivariate analysis adjusting for anatomical site, lymph node extracapsular extension (ECE) and size (T-stage). HICR high-risk tumors were enriched for younger patients with hypoxic tumors (15-gene signature) and elevated 5-miR score. After adjustment for hypoxia and 5-miR covariates, HICR maintained predicting all endpoints. HICR provides a novel mean for assessing the risk of LR in HPV(-) HNSCC patients treated with PORT-C and opens a new opportunity for biomarker-assisted stratification and therapy adaptation in these patients.

RDS data of models developed and reported for the article entitled "Integrated radiogenomics analyses allow for subtype classification and improved outcome prognosis of patients with locally advanced HNSCC". Software package version is also available in repository

Objectives: An MRI- and particle therapy compatible patient-individualized abdominal corset was developed and its efficacy to reduce respiratory-induced pancreas motion was evaluated by orthogonal 2D-cine and 4D-MRI. Patients & Methods: Nine patients (6 female; average age 72.9±9.6 years) with tumors of the pancreas (7), gallbladder (1), or liver (1) provided written informed consent to be scanned on a 3T MRI scanner (Philips Healthcare) by means of orthogonal 2D-cine and 4D-MRI, without and with a patient-individualized abdominal corset, respectively. A polyethylene (PE) abdominal corset (ORD Dresden GmbH) was customized based on an optical 3D-surface scan (Artec Eva®). For MR imaging the patients were positioned supine on a flat tabletop using an anterior coil holder to avoid compression of the chest wall. For 2D-cine MRI, coronal and sagittal slices were selected to image the pancreatic head. The 4D-MRI dataset was reconstructed by retrospectively resorting a multi-slice 2D acquisition into 10 respiratory phases. Pancreas motion was determined as center-of-mass displacement in three orthogonal directions (inferior-superior (IS), anterior-posterior (AP), left-right (LR)). Results and Conclusion: MRI revealed predominant motion in IS direction, which was reduced by 42% (p

Fragestellung: Die intrafraktionelle Bewegung von abdominellen Tumoren erfordert entsprechend große Sicherheitssäume in der Radioonkologie und führt zu einer erhöhten Strahlenbelastung des umliegenden gesunden Gewebes. Für die geplante Magnetresonanztomographie (MRT)-geführte Partikeltherapie (PT) von Pankreaskarzinomen wurde ein innovatives, patientenspezifisches abdominelles Korsett zur Reduktion der atmungsbedingten Pankreasbewegung entwickelt, welches die hohen Materialansprüche der MRT sowie der PT erfüllt. Das Maß an Bewegungsreduktion durch das Korsetts und dessen Verträglichkeit wurde in einer Patientenstudie untersucht. Methodik: Vorbereitend wurden drei abdominelle Korsetts unterschiedlicher Beschaffenheit und Patientenindividualität in ihrer Anwendbarkeit für die MRT-geführte PT bei abdominellen Tumoren untersucht. Das Modell, das die höchste Reproduzierbarkeit in der PT bei Oberbauchtumoren ermöglichte und so eine konformale Strahlentherapie ermöglichte, wurde in einer durch die lokale Ethikkommissioin gebilligte Patientenstudie getestet. Für 12 Patienten (neun weiblich, Alter 71.6±8.6 Jahre) mit Tumoren des Oberbauchs wurde ein Polyethylene-Korsett individuell hergestellt. An einem 3T MRT Scanner wurden von den Patienten sowohl mit Korsett als direkt darauffolgend auch ohne Korsett unter freier Atmung zeitauflösende Bildsequenzen (orthogonale 2D-cine MRT und retrospektiv rekonstruierte 4D-MRT) akquiriert. Das Pankreas wurde in allen Bildern manuell konturiert und die Bewegung des Massenschwerpunktes zwischen maximaler Inspiration und Exspiration in 3D analysiert. Basierend auf einem detaillierten Erhebungsbogen wurde die Verträglichkeit des Korsetts in klinischer Anwendung untersucht. Ergebnis: Durch Applikation des Korsetts wurde bei hoher Patientenverträglichkeit eine Reduktion der Pankreasbewegung vorwiegend in der Hauptrichtung der Atmung (inferior-superior) um 49% (p

This article compares the expression and applicability of biomarkers, from single genes and gene signatures, identified in patients with locally advanced head and neck squamous cell carcinoma using the GeneChip Human Transcriptome Array 2.0, nCounter, and real-time PCR analyses. Two multicenter, retrospective cohorts of patients with head and neck squamous cell carcinoma from the German Cancer Consortium Radiation Oncology Group who received postoperative radiochemotherapy or primary radiochemotherapy were considered. Real-time PCR was performed for a limited number of 38 genes of the cohort who received postoperative radiochemotherapy only. Correlations between the methods were evaluated by the Spearman rank correlation coefficient. Patients were stratified based on the expression of putative cancer stem cell markers, hypoxia-associated gene signatures, and a previously developed seven-gene signature. Locoregional tumor control was compared between these patient subgroups using log-rank tests. Gene expressions obtained from nCounter analyses were moderately correlated to GeneChip analyses (median rho = approximately 0.68). A higher correlation was obtained between nCounter analyses and real-time PCR (median rho = 0.84). Significant associations with locoregional tumor control were observed for most of the considered biomarkers evaluated by GeneChip and nCounter analyses. In general, all applied biomarkers (single genes and gene signatures) classified approximately 70% to 85% of the patients similarly. Overall, gene signatures seem to be more robust and had a better transferability among different measurement methods.

Introduction: In particle beam therapy (PBT) respiratory-induced tumor motion is commonly accounted for by the definition of an internal target volume[1] to cover the tumor in all respiratory phases. Consequentially, also a relatively large volume of healthy tissue surrounding the tumor is exposed to radiation. An appropriate immobilization of the target volume can improve the sparing of healthy tissues. Immobilization of target volumes located in the upper gastro-intestinal tract has been accomplished through abdominal compression bands or pressure plates. These, however, can exacerbate the proton beam range uncertainties when these devices extend into the treatment fields, thereby compromising an accurate dose delivery[2]. For this study, an MR- and PBT-compatible patient-individualized abdominal corset was developed to test its efficacy to reduce respiratory-induced pancreas motion as measured by means of orthogonal 2D-cine and 4D-MRI. Methods: Nine patients (6 female, 3 male; average age 72.9 ± 9.6 years) with abdominal tumors of the pancreas (7 patients), gallbladder (1 patient), or liver (1 patient) provided written informed consent (study number DRKS00010966) to be scanned by means of orthogonal 2D-cine (2 min acquisition time) and 4D-MRI (9 min acquisition time) utilizing a balanced steady-state free precession sequence. For 2D-cine MRI coronal and sagittal slices were positioned to image the pancreatic head. The 4D-MRI dataset was reconstructed by retrospectively resorting a multi-slice 2D acquisition into 10 respiratory phases by amplitude based sorting[3], thereby imaging the full volume of the pancreas. Two MRI scans were acquired per patient, one without and one with a patient-individualized abdominal corset to reduce respiratory motion. The corset was manufactured from polyethylene (Orthopädie- und Rehatechnik Dresden GmbH, Dresden, Germany) based on an optical 3D-surface scan of the patient (Artec Eva®, Artec3D, Luxembourg, Luxemburg). From the nine patients, eight orthogonal 2D-cine datasets and seven 4D-MRI datasets were successfully acquired on a 3.0T MRI scanner (Ingenuity TF PET/MR scanner, Philips Healthcare, Best, The Netherlands). The patients were scanned in supine position on a flat tabletop using an anterior coil holder to avoid anatomical deformations of the chest wall due to the weight of the receiver coils. Pancreas motion was determined as center-of-mass displacement in three orthogonal directions (inferior-superior (IS), anterior-posterior (AP), left-right (LR)) for both orthogonal 2D-cine and 4D-MRI (Fig. 1). The motion amplitude extracted from the 2D-cine dataset was evaluated as the mean peak-to-peak amplitude M95, for which the lower and upper 2.5 % of the data was discarded to reduce the effect of possible outliers. Results: Orthogonal 2D-cine MRI showed that pancreas motion was dominant in IS direction (Fig. 2). For the 8 patients analyzed, the abdominal corset reduced the motion M95 in IS direction by in average 42 % (5 mm ± 3.7 mm (standard deviation) without corset, 3.8 mm ± 1.1 mm with corset; p

Objective: Classical robust optimization (cRO) in intensity-modulated proton therapy (IMPT) considers isocenter position and particle range uncertainties; anatomical robust optimization (aRO) aims to consider additional non-rigid positioning variations. This work compares the influence of different uncertainty sources on the robustness of cRO and aRO IMPT plans for head and neck squamous cell carcinoma (HNSCC). Methods: Two IMPT plans were optimized for twenty HNSCC patients who received weekly control CTs (cCT): cRO, using solely the planning CT, and aRO, including two additional cCTs. The robustness of the plans in terms of clinical target volume (CTV) coverage and organ at risk (OAR) sparing was analyzed considering stepwise the influence of (1) non-rigid anatomical variations given by the weekly cCT, (2) with fraction-wise added rigid random setup errors and (3) additional systematic proton range uncertainties. Results: cRO plans presented significantly higher nominal CTV coverage but are outperformed by aRO plans when considering non-rigid anatomical variations only, as cRO and aRO plans presented a median target coverage (D98%) decrease for the low-risk/high-risk CTV of 1.8/1.1 percentage points (pp) and -0.2pp/-0.3pp, respectively. Setup and range uncertainties had larger influence on cRO CTV coverage, but led to similar OAR dose changes in both plans. Considering all error sources, 10/2 cRO/aRO patients missed the CTV coverage and a limited number exceeded some OAR constraints in both plans. Conclusions: Non-rigid anatomical variations are mainly responsible for critical target coverage loss of cRO plans, whereas the aRO approach was robust against such variations. Both plans provide similar robustness of OAR parameters. Advances in knowledge: The influence of different uncertainty sources was quantified for robust IMPT HNSCC plans.

Purpose/Objective Classical robust optimization considers uncertainties in patient setup and particle range. Usually plan robustness is evaluated from calculation of perturbed dose distributions based on the planning CT, without considering potential anatomical changes that may occur during the treatment course. Our aim was to compare the overall plan robustness of classical robust optimization (cRO) with the recently proposed anatomical robust optimization (aRO) based on an integral multi-scenario evaluation, considering all types of uncertainties including anatomical variations. Material/Methods Datasets for 20 head and neck cancer patients, including a planning CT and weekly control CTs, were analyzed. Two intensity-modulated proton therapy (IMPT) plans were calculated: cRO, using solely the planning CT, and aRO, including additionally the first two control CTs in the plan optimization. For the robustness analysis, perturbed dose distributions with random setup uncertainties and fixed range uncertainty values of -3.5%, 0% and +3.5% were generated, drawing for each fraction n a random number from a Gaussian distribution around 0 mm with a standard deviation of 2.5 mm for the isocenter shift in each cardinal direction (xn, yn, zn). Moreover, in each fraction n the correspondent weekly control CT was used to consider the anatomical changes during therapy. 33 single-fraction perturbed doses were calculated and summed to generate a perturbed whole-treatment dose distribution. The procedure was repeated 10 times for each of the three range uncertainty values, resulting in 30 perturbed dose distributions per plan (Figure 1). Results Both nominal plans fulfilled the clinical objective for target coverage (D98% ≥ 95% of the prescribed dose). The median values calculated from the 30 perturbed dose distributions for each patient showed a reduction in the target coverage for the cRO plan, with mean (minimum) values of 94.9% (88.1%) and 95.4% (89.3%) for the low- and high-risk CTV, respectively, in comparison with 96.6% (92.0%) and 96.8% (93.6%), respectively, for aRO (Figure 2a). The variation in CTV coverage between the 30 scenarios, i.e. the width of the perturbed dose distributions, was found to be larger for cRO plans, with median (maximum) values of 1.9 (8.3) and 1.4 (5.6) for low- and high-risk CTV, respectively, in comparison with 1.4 (3.4) and 0.9 (5.2) for aRO plans, respectively. Moreover, the cRO case showed reduced robustness in comparison with aRO for some patients, where certain scenarios violate the clinical objective, as shown in Figure 2b. Conclusion Anatomical robust optimization showed superior plan robustness in comparison with the classical approach in a comprehensive multi-scenario evaluation. Anatomical variations play an important role in the overall plan robustness together with setup and range uncertainties, therefore their effect should not be underestimated or neglected.

Classical robust optimization considers uncertainties in patient setup and particle range. Usually plan robustness is evaluated from calculation of perturbed dose distributions based on the planning CT, without considering potential anatomical changes that may occur during the treatment course. Our aim was to compare the overall plan robustness of classical robust optimization (cRO) with the recently proposed anatomical robust optimization (aRO) based on an integral multi-scenario evaluation, considering all types of uncertainties including anatomical variations.

Purpose/Objective: In order to improve radiotherapy outcomes, further treatment personalisation is considered beneficial. Radiomics analyses aim to predict treatment outcomes based on medical imaging data. Commonly, hand-crafted imaging features are used that require domain knowledge and further feature selection steps. This may cause relevant information to be lost. Deep convolutional neural networks (CNNs) on the other hand can act as automatic feature detectors and are able to learn highly nonlinear relationships directly from imaging data, thus addressing the drawbacks of conventional radiomics approaches and enabling end-to-end learning. We investigated whether CNNs are capable of quantifying loco-regional tumour control (LRC) based on CT imaging of patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Material/Methods: A multicentre cohort consisting of 302 patients with locally advanced HNSCC was collected and divided into an exploratory and a validation cohort (207 and 95 patients, respectively). All patients received a non-contrast-enhanced CT scan for treatment-planning and were treated by primary radio(chemo)therapy. 9725 transverse CT slices from the exploratory cohort were used to train a CNN with eight convolutional layers. For every patient (with one exception) we used 23 CT slices cranial and caudal of the slice with the largest tumour area, resulting in 47 slices per patient. Discriminative performance was evaluated using 4465 slices of the validation data set. The hazard of loco-regional recurrence was estimated by the CNN maximising the likelihood of the Cox proportional hazards model, which allows for incorporation of nonlinear relationships between the imaging features and the hazard prediction. The final hazard for every patient was obtained by averaging the results of the individual slices. The prognostic value of the model was evaluated by the concordance index (C-Index). Patients were stratified into groups of low and high risk of recurrence using the median hazard in the exploratory cohort. Results: The validation of our CNN model revealed a C-Index of 0.68 (95% confidence interval: 0.57-0.79) for the prognosis of LRC. The estimated hazards were used to stratify patients into two risk groups. LRC significantly differed between these groups, both in the exploratory and the validation cohort (log-rank p

Background: Tumour mutational burden (TMB) estimated from whole exome sequencing or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICIs). Its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI, remains unknown. Methods: The accuracy of TMB estimation by an in-house 327-gene panel was established in the Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) data set. Interference of TMB with outcome after cCRTX was determined in a multicentre cohort of patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumour samples. In a subset of cases (n = 40), tumour RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, human papilloma virus (HPV) status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort. Results: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P = 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort. Conclusion: High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations.

In prostate cancer, disease progression after primary treatment and subsequent androgen deprivation therapy is common. Intensification of systemic treatment is the standard of care. Recently, 68[16_TD$DIFF]Ga prostate-specific membrane antigen positron emission tomography (PSMA-PET) imaging was introduced to identify oligometastatic prostate cancer patients. In this retrospective, exploratory study, we report on the efficacy of PSMA-PET-guided local ablative radiotherapy (aRT) in 15 oligometastatic castrationresistant prostate cancer (CRPC) patients, selected from our prospective institutional database and treated between 2013 and 2016. After multidisciplinary discussion, aRT was delivered with two different schedules. Androgen deprivation therapy remained unchanged. Prostate-specific antigen (PSA) response and time to PSA progression were analysed. For comparison, individual time to PSA progression without aRT was estimated by individual PSA doubling time (PSADT). PSA response was observed in 11 patients (73%). Mean time to PSA progression or last follow-up was 17.9 mo, as opposed to 2.9 mo estimated from the PSADT without aRT (p 12 mo.

Purpose/Objective: The irradiation of tumors, which are subject to respiration-induced motion is challenging for pencil beam scanning (PBS) based proton therapy due to the interplay effect and the temporally varying tissue densities along the beam path. Here, we report on the feasibility, tolerability and setup reproducibility of an individualized immobilization device for patients with tumors in the upper abdomen, who are treated with PBS. Material/Methods: Since January 2018, nine patients with tumors in the upper abdomen (pancreas, liver and gall bladder) have been treated with PBS at our department. All patients eligible for this study underwent the following procedure within 10-days: (1) intra-tumoral implantation of three fiducial markers for target localization, (2) design of an individualized abdominal corset for motion reduction by abdominal compression, (3) abdominal MRI scan with intravenous contrast agent (c.a.) for target volume definition and tumor motion quantification, and (4) 4D-CT scan with c.a. for treatment planning. CT simulation and irradiation was performed with a vacuum mattress (Fig.1). Before each treatment fraction, the position of the target volume was verified with orthogonal X-ray imaging. First, a 2D/2D match with the DRRs was performed and then the position of the fiducial markers was verified (tolerance level: 3-5mm). In case this tolerance level was exceeded, a CT scan was performed in-room and the dose distribution was recalculated for plan comparison; in case of clinically relevant changes in the dose distribution, a new plan was calculated. Result: All patients tolerated the marker implantation, the abdominal corset and the treatment well with no treatment interruptions. In 4 out of the 300 applied fractions (1,3%) the tolerance level of the fiducial markers was exceeded. For these fractions, the recalculated dose distribution nevertheless showed sufficient target coverage (Fig. 2). The entire treatment fraction (including patient positioning, setup verification and dose delivery) did not exceed the standard time slot of 30 minutes. Conclusion: This study demonstrates that PBS-based proton therapy with an abdominal corset to reduce breathing motion of GI-tumors is feasible, well-tolerated by patients and provides a reproducible setup without prolonging the daily treatment time.

Radiotherapy and oncology 127(Supplement 1), PV-0043 (2018). doi:10.1016/S0167-8140(18)30353-0 special issue: "ESTRO 37, April 20-24, 2018, Barcelona, Spain", Published by Elsevier Science, Amsterdam [u.a.]

Purpose/Objective Robust optimization in proton therapy considers uncertainties in patient setup and particle range during the plan optimization. In general, however, anatomical changes occurring during the treatment course, potentially causing a degradation of the plan quality, are neglected. The aim of this study was to quantify the influence of these changes on the dose distribution for patients with bilateral head and neck cancer (HNC). Material/Methods Datasets from 20 HNC patients, consisting of a planning CT and weekly control CTs (cCT), were analyzed. Intensity-modulated proton therapy (IMPT) plans with minimax robust optimization were calculated, accounting 3 mm and 3.5% for setup and range uncertainty, respectively. Prescribed doses to the low- and high-risk clinical target volume (CTV) were 57 and 70 Gy(RBE), respectively, delivered in 33 fractions. The organs at risk (OAR) spinal cord, brainstem, parotid glands, larynx, pharyngeal constrictor and esophageal inlet muscle were considered for plan optimization. Weekly cumulative doses, taking the anatomical variations of the cCTs into account, were compared with the nominal plan. When a reduction in target coverage and/or increased dose to OARs was detected, a plan adaptation was performed on the cCT where the dose degradation was observed. Furthermore, for these patients an additional robust plan was calculated, taking also anatomical changes from the first two cCTs into account in the robust optimization. It was evaluated if a subsequent plan adaptation would still be necessary. Results Nominal plans fulfilled the clinical specifications of D98% ≥ 95% of the prescribed dose to the CTVs (range 96.58-98.81% for low-risk CTV and 96.83-98.76% for high-risk CTV). During the treatment course, anatomical changes lead to reduced weekly cumulative D98% values in five patients (25%; minimum 90.17% for low-risk CTV and 89.19% for high-risk CTV). Doses in OARs remained below the clinical constrains during the treatment course. One treatment adaptation was performed for each of these five patients, which allowed a target coverage improvement (range 97.68-99.72% for low-risk CTV and 95.89-98.46% for high-risk CTV). Total cumulative doses including adaptation were acceptable (range 96.67-98.37% for low-risk CTV and 95.11-97.39% for high-risk CTV, see Figure 1a). The results for the more sophisticated robust plan, considering the first two cCTs, were diverse: whereas plan adaption became obsolete in one patient, the total cumulative dose would, without adaptation, still have been below clinical constraints in another (Figure 1b and 2). Conclusion In a substantial number of patients, robust optimization only is not sufficient to account for anatomical changes occurring during the treatment course, resulting in severe target coverage degradation. Assessment of the cumulative weekly doses allowed detection of target coverage loss. The importance of frequent in-treatment imaging is underlined.

Fragestellung: Die kurativ intendierte Therapie von Patienten mit operablen Kopf-Hals-Plattenepithelkarzinomen erfolgt entsprechend der TNM-Klassifikation: Patienten mit lokal fortgeschrittenen, aber funktionell operablen Kopf-Hals-Tumoren erhalten eine postoperative Radio(chemo)therapie, während bei Patienten mit Tumoren im UICC Stadium I und II eine alleinige Operation durchgeführt wird . Dennoch sprechen die Patienten trotz gleichem Tumorstadium und gleicher Histologie heterogen auf die Standardtherapien an . Für atienten mit lokal fortgeschrittenen Tumoren konnte in einer multizentrischen Studie der Radioonkologie-Gruppe des Deutschen Konsortiums für Translationale Radioonkologie (DKTK-ROG) gezeigt werden, dass der HPV-Status und weitere Biomarker, wie beispielsweise Krebsstammzellmarker und Hypoxie-assoziierte Gensignaturen, wichtige Prognosefaktoren für die lokoregionale Tumorkontrolle nach postoperativer Radiochemotherapie darstellen . Diese Studie hat das Ziel zu untersuchen, ob dieselben prognostischen Faktoren auch für Patienten mit lokal begrenzten Tumoren relevant sind, die eine alleinige Operation erhalten. Methodik: In dieser retrospektiven, monozentrischen Studie wurden 174 Patienten mit einem zwischen 2005 bis 2014 diagnostizierten lokal begrenzten Plattenepithelkarzinom (Mundhöhle, Oropharynx, Hypopharynx) eingeschlossen, die eine alleinige Operation in kurativer Intention erhalten haben . Die Proteinexpressionen des HPV-Surrogatmarkers 16 und des Krebsstammzellmarkers CD44 wurden immunhistochemisch bestimmt . Der HPV DNA Nachweis erfolgte mittels eines PCR-basierten Arrays. Enexpressionsanalysen des Markers CD44 sowie von Hypoxie-assoziierten Gensignaturen wurden mittels nanoString-Technologie durchgeführt . Endpunkte waren die lokale Tumorkontrolle (LK) und die regionale Tumorkontrolle (RK) . Ergebnisse: Alle Patienten mit p16-positiven Tumoren zeigten eine vollständige RK im Vergleich zu den Patienten mit p16-negativen Tumoren (p = 0,102) . Es konnten aber nur 27,3 % der p16-positiven Tumoren positiv für HPV DNA getestet werden (22,7 % HPV16 DNA; 4,5 % HPV33 DNA) . Patienten mit CD44-positiven Tumoren zeigten eine schlechtere LK als Patienten mit CD44-negativen Tumoren, insbesondere war eine hohe CD44-Positivität der Tumorzellen (>65 % der Tumorzellen) signifikant mit dem Auftreten von Lokalrezidiven assoziiert (p = 0,005) . Eine erhöhte CD44-Genexpression zeigte ebenfalls eine signifikant schlechtere LK (p = 0,036) . Die Analyse von Hypoxie-assoziierten Gensignaturen zeigte jedoch keinen Einfluss auf die Endpunkte. Schlussfolgerung: Diese Analysen zeigen, dass p16 und CD44 auch bei lokal begrenzten Tumoren potentielle prognostische Biomarker darstellen und, nach erfolgreicher Validierung in der aktuell rekrutierenden HNbioSUR-Studie, möglicherweise für die Individualisierung der Therapie eingesetzt werden können.

Radiotherapy and oncology 127(Supplement 1), PV-044 (2018). doi:10.1016/S0167-8140(18)30354-2 special issue: "ESTRO 37, April 20-24, 2018, Barcelona, Spain", Published by Elsevier Science, Amsterdam [u.a.]

Purpose/Objective: Radiomics aims to characterise the tumour phenotype using advanced image features to predict patient-specific outcome. Commonly, image features are calculated from the entire gross tumour volume (GTVe). However, tumours are biologically complex, e.g., expressing necrosis merely in the core and tumour cell proliferation at the periphery. The identification of sub-volumes to incorporate regional tumour variation into the risk models may lead to an improved outcome prediction. Therefore, we investigated different sub-volumes of the GTVe using CT imaging, developed radiomic signatures, and compared prognostic power and stratification performance of the signatures. Material/Methods: A multicentre cohort consisting of 302 patients with advanced stage head and neck squamous cell carcinoma (HNSCC) was collected and divided into an exploratory and a validation cohort (208 and 94 patients, respectively). All patients received primary radio-chemotherapy at one of the six DKTK partner sites and underwent a non-contrast-enhanced CT scan for treatment-planning purposes. The analysis was divided into two subsequent steps (Fig. 1): (a) two distinct sub-regions were extracted from GTVe: the tumour boundary of different widths (3,5,10 mm) and the corresponding remaining core volumes. (b) extension of the highest prognostic tumour-boundary sub-volume by different widths (1,2,3,5 mm) beyond the GTVe. 1555 image features were extracted from each sub-volume. Different machine-learning algorithms were used to build radiomic models for the prediction of loco-regional tumour control (LRC). The prognostic performance was measured by the concordance index (C-Index). Finally, patients were stratified into groups of low and high risk of recurrence using the median risk value. Differences in LRC were evaluated by log-rank tests. Results: The validation C-Index averaged over all learning algorithms and feature selection methods using the GTVe revealed a high prognostic performance for LRC (C-Index: 0.63±0.03 (mean±std)). The boundary sub-volumes GTV5mm and GTV10mm showed a slightly improved accuracy (C-Index: 0.64±0.03 and 0.64±0.02, respectively), while models based on the corresponding core volumes had a lower accuracy (C-Index: 0.59±0.03 and 0.60±0.03, respectively, (Fig. 2A)). Also the risk groups could be better separated using the GTV5mm (p

Purpose: To improve compare and improve the performance of a hypothesis-driven 7-gene signature by with a signature based on whole transcriptome analysis for the prognosis of loco-regional tumour control (LRC) in patients with HPV-negative locally advanced head and neck squamous cell carcinoma (HNSCC) after postoperative radiochemotherapy (PORT-C). Material and methods: Gene expression analyses were performed on a multicentre retrospective cohort of 125 patients with HPV16 DNA negative HNSCC using the GeneChip® Human Transcriptome Array 2.0 (Affymetrix) for whole transcriptome analysis. To identify a gene signature prognostic for LRC from the whole transcriptome data, 3085 genes were considered, which previously have been related to radioresistance or response to radiotherapy [1-4]. The final gene signature was based on the comparison of different signature sizes, feature selection algorithms and prognostic models. The performance of the whole transcriptome-based signature was compared to a previously identified 7-gene signature based on nanoString analysis of a hypothesis-driven gene set containing 171 genes, using the concordance index (ci). The signatures were applied independently and combined to stratify patients into groups of low (LR) and high (HR) risk of recurrence. Results: The identified gene signatures based on whole transcriptome data showed improved performance (ci 0.79-0.87) compared to the signatures based on the hypothesis-driven gene set (0.72-0.78). The model with the best performing gene signature contained genes related to tumourigenesis, invasion, cell cycle regulation and immune response. Patient stratification into low and high risk groups was performed for both signatures, see figures (A) and (B). The difference in LRC between both groups was highly significant (p

Tumor cells frequently overexpress heat shock protein 70 (Hsp70) and present it on their cell surface, where it can be recognized by pre-activated NK cells. In our retrospective study the expression of Hsp70 was determined in relation to tumor-infiltrating CD56+ NK cells in formalin-fixed paraffin embedded (FFPE) tumor specimens of patients with SCCHN (N = 145) as potential indicators for survival and disease recurrence. All patients received radical surgery and postoperative cisplatin-based radiochemotherapy (RCT). In general, Hsp70 expression was stronger, but with variable intensities, in tumor compared to normal tissues. Patients with high Hsp70 expressing tumors (scores 3-4) showed significantly decreased overall survival (OS; p = 0.008), local progression-free survival (LPFS; p = 0.034) and distant metastases-free survival (DMFS; p = 0.044), compared to those with low Hsp70 expression (scores 0-2), which remained significant after adjustment for relevant prognostic variables. The adverse prognostic value of a high Hsp70 expression for OS was also observed in patient cohorts with p16- (p = 0.001), p53- (p = 0.0003) and HPV16 DNA-negative (p = 0.001) tumors. The absence or low numbers of tumor-infiltrating CD56+ NK cells also correlated with significantly decreased OS (p = 0.0001), LPFS (p = 0.0009) and DMFS (p = 0.0001). A high Hsp70 expression and low numbers of tumor-infiltrating NK cells have the highest negative predictive value (p = 0.00004). In summary, a strong Hsp70 expression and low numbers of tumor-infiltrating NK cells correlate with unfavorable outcome following surgery and RCT in patients with SCCHN, and thus serve as negative prognostic markers.