Neuroprotection in radiotherapy of brain metastases: A pattern-of-care analysis in Germany, Austria and Switzerland by the German Society for radiation Oncology - working group Neuro-Radio-Oncology (DEGRO AG-NRO).

Background and purpose: Many patients with solid tumors develop brain metastases (BM). With more patients surviving long-term, preservation of neurocognitive function gains importance. In recent years, several methods to delay cognitive deterioration have been tested in clinical trials. However, knowledge on the extent to which these neuroprotective strategies have been implemented in clinical practice is missing. Materials and methods: We performed an online survey regarding treatment patterns of BM in German-speaking countries, focused on the use of neuroprotective approaches. The survey was distributed among radiation oncologists (ROs) registered within the database of the German Society for Radiation Oncology (DEGRO). Results: Physicians of 78 centers participated in the survey. Whole brain radiotherapy (WBRT) is still preferred by 70 % of ROs over stereotactic radiotherapy (SRT) in patients with 6-10 BM. For 4-5 BM WBRT is preferred by 23 % of ROs. The fraction of ROs using hippocampal sparing (HS) in WBRT has increased to 89 %, although the technique is used on a regular basis only by a minority (26 %). The drug memantine is not widely prescribed (14% of ROs). A trend was observed for university hospitals to implement neuroprotective approaches more frequently. Conclusion: There is considerable heterogeneity regarding the treatment of BM in German-speaking countries and a general standard of care is lacking. Neuroprotective strategies are not yet standard approaches in daily clinical routine, although usage is increasing. Further clinical trials, as well as improvement of technical opportunities and reimbursement, might further shift the treatment landscape towards neuroprotective radiation treatments in the future.

TRIB1 confers therapeutic resistance in GBM cells by activating the ERK and Akt pathways.

GBM (Glioblastoma) is the most lethal CNS (Central nervous system) tumor in adults, which inevitably develops resistance to standard treatments leading to recurrence and mortality. TRIB1 is a serine/threonine pseudokinase which functions as a scaffold platform that initiates degradation of its substrates like C/EBPα through the ubiquitin proteasome system and also activates MEK and Akt signaling. We found that increased TRIB1 gene expression associated with worse overall survival of GBM patients across multiple cohorts. Importantly, overexpression of TRIB1 decreased RT/TMZ (radiation therapy/temozolomide)-induced apoptosis in patient derived GBM cell lines in vitro. TRIB1 directly bound to MEK and Akt and increased ERK and Akt phosphorylation/activation. We also found that TRIB1 protein expression was maximal during G2/M transition of cell cycle in GBM cells. Furthermore, TRIB1 bound directly to HDAC1 and p53. Importantly, mice bearing TRIB1 overexpressing tumors had worse overall survival. Collectively, these data suggest that TRIB1 induces resistance of GBM cells to RT/TMZ treatments by activating the cell proliferation and survival pathways thus providing an opportunity for developing new targeted therapeutics.

Feasibility, pitfalls and results of a structured concept-development phase for a randomized controlled phase III trial on radiotherapy in primary prostate cancer patients.

OBJECTIVE: Failure rate in randomized controlled trials (RCTs) is > 50%, includes safety-problems, underpowered statistics, lack of efficacy, lack of funding or insufficient patient recruitment and is even more pronounced in oncology trials. We present results of a structured concept-development phase (CDP) for a phase III RCT on personalized radiotherapy (RT) in primary prostate cancer (PCa) patients implementing prostate specific membrane antigen targeting positron emission tomography (PSMA-PET). MATERIALS AND METHODS: The 1 yr process of the CDP contained five main working packages: (i) literature search and scoping review, (ii) involvement of individual patients, patients' representatives and patients' self-help groups addressing the patients' willingness to participate in the preparation process and the conduct of RCTs as well as the patient informed consent (PIC), (iii) involvement of national and international experts and expert panels (iv) a phase II pilot study investigating the safety of implementation of PSMA-PET for focal dose escalation RT and (v) in-silico RT planning studies assessing feasibility of envisaged dose regimens and effects of urethral sparing in focal dose escalation. RESULTS: (i) Systematic literature searches confirmed the high clinical relevance for more evidence on advanced RT approaches, in particular stereotactic body RT, in high-risk PCa patients. (ii) Involvement of patients, patient representatives and randomly selected males relevantly changed the PIC and initiated a patient empowerment project for training of bladder preparation. (iii) Discussion with national and international experts led to adaptions of inclusion and exclusion criteria. (iv) Fifty patients were treated in the pilot trial and in- and exclusion criteria as well as enrollment calculations were adapted accordingly. Parallel conduction of the pilot trial revealed pitfalls on practicability and broadened the horizon for translational projects. (v) In-silico planning studies confirmed feasibility of envisaged dose prescription. Despite large prostate- and boost-volumes of up to 66% of the prostate, adherence to stringent anorectal dose constraints was feasible. Urethral sparing increased the therapeutic ratio. CONCLUSION: The dynamic framework of interdisciplinary working programs in CDPs enhances robustness of RCT protocols and may be associated with decreased failure rates. Structured recommendations are warranted to further define the process of such CDPs in radiation oncology trials.

Evaluation of prognostic factors after primary chemoradiotherapy of anal cancer: A multicenter study of the German Cancer Consortium-Radiation Oncology Group (DKTK-ROG).

BACKGROUND AND PURPOSE: Prognosis after chemoradiotherapy (CRT) for anal squamous cell carcinoma (ASCC) shows marked differences among patients according to TNM subgroups, however individualized risk assessment tools to better stratify patients for treatment (de-) escalation or intensified follow-up are lacking in ASCC. MATERIALS AND METHODS: Patients' data from eight sites of the German Cancer Consortium - Radiation Oncology Group (DKTK-ROG), comprising a total of 605 patients with ASCC, treated with standard definitive CRT with 5-FU/Mitomycin C or Capecitabine/Mitomycin C between 2004-2018, were used to evaluate prognostic factors based on Cox regression models for disease-free survival (DFS). Evaluated variables included age, gender, Karnofsky performance score (KPS), HIV-status, T-category, lymph node status and laboratory parameters. Multivariate cox models were separately constructed for the whole cohort and the subset of patients with early-stage (cT1-2 N0M0) tumors. RESULTS: After a median follow-up of 46 months, 3-year DFS for patients with early-stage ASCC was 84.9%, and 67.1% for patients with locally-advanced disease (HR 2.4, p < 0.001). T-category (HR vs. T1: T2 2.02; T3 2.11; T4 3.03), N-category (HR versus N0: 1.8 for N1-3), age (HR 1.02 per year), and KPS (HR 0.8 per step) were significant predictors for DFS in multivariate analysis in the entire cohort. The model performed with a C-index of 0.68. In cT1-2N0 patients, T-category (HR 2.14), HIV status (HR 2.57), age (1.026 per year), KPS (HR 0.7 per step) and elevated platelets (HR 1.3 per 100/nl) were associated with worse DFS (C-index of 0.7). CONCLUSION: Classical clinicopathologic parameters like T-category, N-category, age and KPS remain to be significant prognostic factors for DFS in patients treated with contemporary CRT for ASCC. HIV and platelets were significantly associated with worse DFS in patients with early stage ASCC.

Integration of radiation oncology teaching in medical studies by German medical faculties due to the new licensing regulations : An overview and recommendations of the consortium academic radiation oncology of the German Society for Radiation Oncology (DEGRO).

The new Medical Licensing Regulations 2025 (Ärztliche Approbationsordnung, ÄApprO) will soon be passed by the Federal Council (Bundesrat) and will be implemented step by step by the individual faculties in the coming months. The further development of medical studies essentially involves an orientation from fact-based to competence-based learning and focuses on practical, longitudinal and interdisciplinary training. Radiation oncology and radiation therapy are important components of therapeutic oncology and are of great importance for public health, both clinically and epidemiologically, and therefore should be given appropriate attention in medical education. This report is based on a recent survey on the current state of radiation therapy teaching at university hospitals in Germany as well as the contents of the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog Medizin 2.0, NKLM) and the closely related Subject Catalogue (Gegenstandskatalog, GK) of the Institute for Medical and Pharmaceutical Examination Questions (Institut für Medizinische und Pharmazeutische Prüfungsfragen, IMPP). The current recommendations of the German Society for Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO) regarding topics, scope and rationale for the establishment of radiation oncology teaching at the respective faculties are also included.

Combined radiotherapy and concurrent tumor treating fields (TTFields) for glioblastoma: Dosimetric consequences on non-coplanar IMRT as initial results from a phase I trial.

BACKGROUND: Glioblastoma is a rapidly proliferating tumor. Patients bear an inferior prognosis with a median survival time of 14-16 months. Proliferation and repopulation are a major resistance promoting factor for conventionally fractionated radiotherapy. Tumor-Treating-Fields (TTFields) are an antimitotic modality applying low-intensity (1-3 V/cm), intermediate-frequency (100-300 kHz) alternating electric-fields. More recently interference of TTFields with DNA-damage-repair and synergistic effects with radiotherapy were reported in the preclinical setting. This study aims at examining the dosimetric consequences of TTFields applied during the course of radiochemotherapy. METHODS: Cone-beam-computed-tomography (CBCT)-data from the first seven patients of the PriCoTTF-phase-I-trial were used in a predefined way for dosimetric verification and dose-accumulation of the non-coplanar-intensity-modulated-radiotherapy (IMRT)-treatment-plans as well as geometric analysis of the transducer-arrays by which TTFields are applied throughout the course of treatment. Transducer-array-position and contours were obtained from the low-dose CBCT's routinely made for image-guidance. Material-composition of the electrodes was determined and a respective Hounsfield-unit was assigned to the electrodes. After 6D-fusion with the planning-CT, the dose-distribution was recalculated using a Boltzmann-equation-solver (Acuros XB) and a Monte-Carlo-dose-calculation-engine. RESULTS: Overdosage in the scalp in comparison to the treatment plan without electrodes stayed below 8.5% of the prescribed dose in the first 2 mm below and also in deeper layers outside 1cm2 at highest dose as obtained from dose-volume-histogram comparisons. In the clinical target volume (CTV), underdosage was limited to 2.0% due to dose attenuation by the electrodes in terms of D95 and the effective-uniform-dose. Principal-component-analysis (PCA) showed that the first principal-position-component of the variation of repeated array-placement in the direction of the largest variations and the perpendicular second-component spanning a tangential plane on the skull had a standard deviation of 1.06 cm, 1.23 cm, 0.96 cm, and 1.11 cm for the frontal, occipital, left and right arrays for the first and 0.70 cm, 0.71 cm, 0.79 cm, and 0.68 cm, respectively for the second-principal-component. The variations did not differ from patient-to-patient (p > 0.8, Kruskal-Wallis-tests). This motion led to a diminution of the dosimetric effects of the electrodes. CONCLUSION: From a dosimetric point of view, dose deviations in the CTV due to transducer-arrays were not clinically significant in the first 7 patients and confirmed feasibility of combined adjuvant radiochemotherapy and concurrent TTFields. PriCoTTF Trial: A phase I/II trial of TTFields prior and concomitant to radiotherapy in newly diagnosed glioblastoma. DRKS-ID: DRKS00016667. Date of Registration in DRKS: 2019/02/26. Investigator Sponsored/Initiated Trial (IST/IIT): yes. Ethics Approval/Approval of the Ethics Committee: Approved. (leading) Ethics Committee Nr.: 18-8316-MF, Ethik-Kommission der Medizinischen. Fakultät der Universität Duisburg-Essen. EUDAMED-No. (for studies acc. to Medical Devices act): CIV-18-08-025247.

Recent advances of PET imaging in clinical radiation oncology.

Radiotherapy and radiation oncology play a key role in the clinical management of patients suffering from oncological diseases. In clinical routine, anatomic imaging such as contrast-enhanced CT and MRI are widely available and are usually used to improve the target volume delineation for subsequent radiotherapy. Moreover, these modalities are also used for treatment monitoring after radiotherapy. However, some diagnostic questions cannot be sufficiently addressed by the mere use standard morphological imaging. Therefore, positron emission tomography (PET) imaging gains increasing clinical significance in the management of oncological patients undergoing radiotherapy, as PET allows the visualization and quantification of tumoral features on a molecular level beyond the mere morphological extent shown by conventional imaging, such as tumor metabolism or receptor expression. The tumor metabolism or receptor expression information derived from PET can be used as tool for visualization of tumor extent, for assessing response during and after therapy, for prediction of patterns of failure and for definition of the volume in need of dose-escalation. This review focuses on recent and current advances of PET imaging within the field of clinical radiotherapy / radiation oncology in several oncological entities (neuro-oncology, head & neck cancer, lung cancer, gastrointestinal tumors and prostate cancer) with particular emphasis on radiotherapy planning, response assessment after radiotherapy and prognostication.

Influence of localization of PSMA-positive oligo-metastases on efficacy of metastasis-directed external-beam radiotherapy-a multicenter retrospective study.

PURPOSE: Approximately 40-70% of biochemically persistent or recurrent prostate cancer (PCa) patients after radical prostatectomy (RPE) are oligo-metastatic in 68gallium-prostate-specific membrane antigen positron emission tomography (68Ga-PSMA PET). Those lesions are frequently located outside the prostate bed, and therefore not cured by the current standards of care like external-beam radiotherapy (EBRT) of the prostatic fossa. This retrospective study analyzes the influence of oligo-metastases' site on outcome after metastasis-directed radiotherapy (MDR). METHODS: Retrospectively, 359 patients with PET-positive PCa recurrences after RPE were analyzed. Biochemical recurrence-free survival (BRFS) (prostate-specific antigen (PSA) < post-radiotherapy nadir + 0.2 ng/mL) was assessed using Kaplan-Meier survival and Cox regression analysis. RESULTS: All patients were initially clinically without distant metastases (cM0). Seventy-five patients had local recurrence within the prostatic fossa, 32 patients had pelvic nodal plus local recurrence, 117 patients had pelvic nodal recurrence, 51 patients had paraaortic lymph node metastases with/without locoregional recurrence, and 84 patients had bone or visceral metastases with/without locoregional recurrence. Median PSA before MDR was 1.2 ng/mL (range, 0.04-47.5). Additive androgen deprivation therapy (ADT) was given in 35% (125/359) of patients. Median PSA nadir after MDR was 0.23 ng/mL (range, < 0.03-18.30). After a median follow-up of 16 months (1-57), 239/351 (68%) patients had no biochemical recurrence. Patients with distant lymph node and/or distant metastases, the so-called oligo-body cohort, had an overall in-field control of 90/98 (91%) but at the same time, an ex-field progress of 44/96 (46%). In comparison, an ex-field progress was detected in 28/154 (18%) patients with local and/or pelvic nodal recurrence (oligo-pelvis group). Compared with the oligo-pelvis group, there was a significantly lower BRFS in oligo-body patients at the last follow-up. CONCLUSION: Overall, BRFS was dependent on patterns of metastatic disease. Thus, MDR of PSMA PET-positive oligo-metastases can be offered considering that about one-third of the patients progressed within a median follow-up of 16 months.

Quantification of Tumor Oxygenation Based on FMISO PET: Influence of Location and Oxygen Level of the Well-Oxygenated Reference Region.

Tumor hypoxia may play a fundamental role in determining the radiotherapy outcome for several cancer types. Functional imaging with hypoxia specific radiotracers offers a way to visualize and quantify regions of increased radioresistance, which may benefit from dose escalation strategies. Conversion of the uptake in positron emission tomography (PET) images into oxygenation maps offers a way to quantitatively characterize the microenvironment. However, normalization of the uptake with respect to a well-oxygenated reference volume (WOV), which should be properly selected, is necessary when using conversion functions. This study aims at assessing the sensitivity of quantifying tumor oxygenation based on 18F-fluoromisonidazole (FMISO) PET with respect to the choice of the location and the oxygenation level of the WOV in head and neck cancer patients. WOVs varying not only in shape and location but also with respect to the assigned pO2 level were considered. pO2 values other than the standard 60 mmHg were selected according to the specific tissue type included in the volume. For comparison, the volume which would be considered as hypoxic based on a tissue-to-muscle ratio equal to 1.4 was also delineated, as conventionally done in clinical practice. Hypoxia mapping strategies are found highly sensitive to selection of the location of well-oxygenated region, but also on its assigned oxygenation level, which is crucial for hypoxia-guided adaptive dose escalation strategies.

Textural features of hypoxia PET predict survival in head and neck cancer during chemoradiotherapy.

PURPOSE: The aim of this study was to investigate whether textural features of tumour hypoxia, assessed with serial [18F]fluoromisonidazole (FMISO)-PET, were able to predict clinical outcome in patients with head and neck squamous cell carcinoma (HNSCC, T1-4, N+, M0) during chemoradiotherapy (CRT). METHODS: In a preliminary evaluation of a prospective trial, tumour hypoxia was evaluated in 29 patients via serial FMISO-PET before and during CRT. All patients received an initial [18F]fluorodeoxyglucose (FDG)-PET before CRT, and tumour regions were defined on this FDG-PET. The first-order metrics tumour-to-background ratio (TBRmean, TBRmax, TBRpeak), coefficient of variation, total lesion uptake and integral non-uniformity were calculated for all scans. Further, 3 second-order (textural) features from two grey-level matrices were calculated, as well as differential non-uniformity (udiff). Prognostic value was examined by median split for group separation (GS) in Kaplan-Meier estimates and correlated with overall survival (OS), quantified via log-rank tests (p ≤ 0.05) and group-relative hazard ratios (HR). RESULTS: Within a median follow-up of 29.6 months (95% CI: 16.8-48.0 months), no first-order metrics predicted OS with a significant GS (all p > 0.05) on any FMISO-PET scan. Only udiff before and in week 2 during CRT (p = 0.03, HR = 10.8 and p = 0.05, HR = 5.2) and non-uniformity from grey-level run length matrix in week 2 separated prognostic groups (p = 0.05, HR = 5.3); lower values were correlated with better OS. Further, the decrease in udiff from before CRT to week 2 was correlated with better OS (p = 0.04, HR = 9.4). FDG-PET before CRT did not predict outcome in any measure. CONCLUSIONS: Textural features on FMISO-PET scans before CRT, in week 2 and, to a limited degree, the change of features during CRT, were able to identify head and neck squamous cell carcinoma patients with better OS, suggesting that a higher homogeneity of the degree of hypoxia in tumours could correlate with a better outcome after CRT.

Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group.

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.

Combination of stereotactic radiotherapy and targeted therapy: patterns-of-care survey in German-speaking countries.

INTRODUCTION: Stereotactic body radiotherapy (SBRT) is increasingly used in metastasized patients receiving targeted/immunotherapy. Information on safety and effectivity of concurrent SBRT and targeted/immunotherapy remains limited, resulting in a lack of consensus on treatment strategies. This study aimed to investigate how SBRT-experienced centers in German-speaking countries combine both therapies. MATERIALS AND METHODS: Patterns-of-care of combined treatment with SBRT and targeted/immunotherapy were assessed in 27 radiation oncology centers (19 German, 1 Austrian and 7 Swiss centers). A survey was performed to analyze the details of SBRT, SBRT planning and combined modality treatment. Consensus was defined as ≥75% agreement among participants. RESULTS: Most participants (60%) were university centers. SBRT for oligometastases has been performed since the year 2008 (median, range 1997-2016), since then a median of 140 cases (5-1100) of SBRT have been performed. In all, 67% performed concurrent SBRT and targeted agents. BRAF inhibitors and VEGF/EGFR inhibitors (bevacizumab [90%], erlotinib [11%], sorafenib [19%], lapatinib [4%]) were considered a contraindication. Bevacizumab was never given simultaneously with SBRT; other agents were given concurrently in 7-52% of centers. A majority (59%) paused targeted agents 1 week before/after SBRT. Only 1 center reduced SBRT dose when combined with targeted agents. CONCLUSION: Although evidence for safety and efficacy of concurrent SBRT and targeted agents is limited, it is regularly performed outside of clinical trials. The survey showed consensus not to combine SBRT with antiangiogenic agents, especially bevacizumab. Furthermore, SBRT with concurrent BRAF inhibitors should be practiced with caution and BRAF inhibitors should be paused at least 1 week before SBRT.

Standard of Care Versus Metastases-directed Therapy for PET-detected Nodal Oligorecurrent Prostate Cancer Following Multimodality Treatment: A Multi-institutional Case-control Study.

BACKGROUND: Most prostate cancer (PCa) patients with a biochemical failure following primary multimodality treatment (surgery and postoperative radiotherapy) relapse in the nodes. OBJECTIVE: To perform a matched-case analysis in men with lymph node recurrent PCa comparing standard of care (SOC) with metastasis-directed therapy (MDT). DESIGN, SETTING, AND PARTICIPANTS: PCa patients with a prostate-specific antigen (PSA) progression following multimodality treatment were included in this retrospective multi-institutional analysis. INTERVENTION: The SOC cohort (n=1816) received immediate or delayed androgen deprivation therapy administered at PSA progression. The MDT cohort (n=263) received either salvage lymph node dissection (n=166) or stereotactic body radiotherapy (n=97) at PSA progression to a positron emission tomography-detected nodal recurrence. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint, cancer-specific survival (CSS), was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched analyses. RESULTS AND LIMITATIONS: At a median follow-up of 70 (interquartile range: 48-98) mo, MDT was associated with an improved CSS on univariate (p=0.029) and multivariate analysis (hazard ratio: 0.33, 95% confidence interval [CI]: 0.17-0.64) adjusted for the year of radical prostatectomy (RP), age at RP, PSA at RP, time from RP to PSA progression, Gleason score, surgical margin status, pT- and pN-stage. In total, 659 men were matched (3:1 ratio). The 5-yr CSS was 98.6% (95% CI: 94.3-99.6) and 95.7% (95% CI: 93.2-97.3) for MDT and SOC, respectively (p=0.005, log-rank). The main limitations of our study are its retrospective design and lack of standardization of systemic treatment in the SOC cohort. CONCLUSIONS: MDT for nodal oligorecurrent PCa improves CSS as compared with SOC. These retrospective data from a multi-institutional pooled analysis should be considered as hypothesis-generating and inform future randomized trials in this setting. PATIENT SUMMARY: Prostate cancer patients experiencing a lymph node recurrence might benefit from local treatments directed at these lymph nodes.

Proteome Profiling of Primary Pancreatic Ductal Adenocarcinomas Undergoing Additive Chemoradiation Link ALDH1A1 to Early Local Recurrence and Chemoradiation Resistance.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with frequent post-surgical local recurrence. The combination of adjuvant chemotherapy with radiotherapy is under consideration to achieve a prolonged progression-free survival (PFS). To date, few studies have determined the proteome profiles associated with response to adjuvant chemoradiation. We herein analyzed the proteomes of primary PDAC tumors subjected to additive chemoradiation after surgical resection and achieving short PFS (median 6 months) versus prolonged PFS (median 28 months). Proteomic analysis revealed the overexpression of Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) and Monoamine Oxidase A (MAOA) in the short PFS cohort, which were corroborated by immunohistochemistry. In vitro, specific inhibition of ALDH1A1 by A37 in combination with gemcitabine, radiation, and chemoradiation lowered cell viability and augmented cell death in MiaPaCa-2 and Panc 05.04 cells. ALDH1A1 silencing in both cell lines dampened cell proliferation, cell metabolism, and colony formation. In MiaPaCa-2 cells, ALDH1A1 silencing sensitized cells towards treatment with gemcitabine, radiation or chemoradiation. In Panc 05.04, increased cell death was observed upon gemcitabine treatment only. These findings are in line with previous studies that have suggested a role of ALDH1A1 chemoradiation resistance, e.g., in esophageal cancer. In summary, we present one of the first proteome studies to investigate the responsiveness of PDAC to chemoradiation and provide further evidence for a role of ALDH1A1 in therapy resistance.

Comparison of PET/CT and whole-mount histopathology sections of the human prostate: a new strategy for voxel-wise evaluation.

BACKGROUND: Implementation of PET/CT in diagnosis of primary prostate cancer (PCa) requires a profound knowledge about the tracer, preferably from a quantitative evaluation. Direct visual comparison of PET/CT slices to whole prostate sections is hampered by considerable uncertainties from imperfect coregistration and fundamentally different image modalities. In the current study, we present a novel method for advanced voxel-wise comparison of histopathology from excised prostates to pre-surgical PET. Resected prostates from eight patients who underwent PSMA-PET/CT were scanned (ex vivo CT) and thoroughly pathologically prepared. In vivo and ex vivo CT including histopathology were coregistered with three different methods (manual, semi-/automatic). Spatial overlap after CT-based registration was evaluated with dice similarity (DSC). Furthermore, we constructed 3D cancer distribution models from histopathologic information in various slices. Subsequent smoothing reflected the intrinsically limited spatial resolution of PSMA-PET. The resulting histoPET models were used for quantitative analysis of spatial histopathology-PET pattern agreement focusing on p values and coefficients of determination (R 2). We examined additional rigid mutual information (MI) coregistration directly based on PSMA-PET and histoPET. RESULTS: Mean DSC for the three different methods (ManReg, ScalFactReg, and DefReg) were 0.79 ± 0.06, 0.82 ± 0.04, and 0.90 ± 0.02, respectively, while quantification of PET-histopathology pattern agreement after CT-based registration revealed R 2 45.7, 43.2, and 41.3% on average with p < 10-5. Subsequent PET-based MI coregistration yielded R 2 61.3, 55.9, and 55.6%, respectively, while implying anatomically plausible transformations. CONCLUSIONS: Creating 3D histoPET models based on thorough histopathological preparation allowed sophisticated quantitative analyses showing highly significant correlations between histopathology and (PSMA-)PET. We recommend manual CT-based coregistration followed by a PET-based MI algorithm to overcome limitations of purely CT-based coregistrations for meaningful voxel-wise comparisons between PET and histopathology.

Interobserver variability in target volume delineation of hepatocellular carcinoma : An analysis of the working group "Stereotactic Radiotherapy" of the German Society for Radiation Oncology (DEGRO).

BACKGROUND: Definition of gross tumor volume (GTV) in hepatocellular carcinoma (HCC) requires dedicated imaging in multiple contrast medium phases. The aim of this study was to evaluate the interobserver agreement (IOA) in gross tumor delineation of HCC in a multicenter panel. METHODS: The analysis was performed within the "Stereotactic Radiotherapy" working group of the German Society for Radiation Oncology (DEGRO). The GTVs of three anonymized HCC cases were delineated by 16 physicians from nine centers using multiphasic CT scans. In the first case the tumor was well defined. The second patient had multifocal HCC (one conglomerate and one peripheral tumor) and was previously treated with transarterial chemoembolization (TACE). The peripheral lesion was adjacent to the previous TACE site. The last patient had an extensive HCC with a portal vein thrombosis (PVT) and an inhomogeneous liver parenchyma due to cirrhosis. The IOA was evaluated according to Landis and Koch. RESULTS: The IOA for the first case was excellent (kappa: 0.85); for the second case moderate (kappa: 0.48) for the peripheral tumor and substantial (kappa: 0.73) for the conglomerate. In the case of the peripheral tumor the inconsistency is most likely explained by the necrotic tumor cavity after TACE caudal to the viable tumor. In the last case the IOA was fair, with a kappa of 0.34, with significant heterogeneity concerning the borders of the tumor and the PVT. CONCLUSION: The IOA was very good among the cases were the tumor was well defined. In complex cases, where the tumor did not show the typical characteristics, or in cases with Lipiodol (Guerbet, Paris, France) deposits, IOA agreement was compromised.

The TNM 8 M1b and M1c classification for non-small cell lung cancer in a cohort of patients with brain metastases.

BACKGROUND AND PURPOSE: According to the recent TNM 8 classification, patients with metastatic non-small cell lung cancer (NSCLC) and single extrathoracic metastasis should be classified as stage M1b, while those with 2 or more metastases comprise stage M1c. The purpose of this study was to analyze the impact of this classification in patients with brain metastases. MATERIALS AND METHODS: This retrospective study included 172 patients treated with individualized approaches. Actuarial survival was calculated. Uni- and multivariate analyses were performed. RESULTS: Thirty patients (17%) were staged as M1b. Those with squamous cell cancer were more likely to harbor M1b disease (29%, adenocarcinoma 14%, other histology 17%, p = 0.16). Median survival was 5.4 months (8.0 months in case of M1b disease and 4.5 months in case of M1c disease, p = 0.001). Multivariate analysis confirmed the role of M1b stage. M1b patients managed with upfront surgery or radiosurgery had significantly longer median survival than those who received whole-brain irradiation (21.0 vs. 3.5 months, p = 0.0001) and the potential to survive beyond 5 years. CONCLUSIONS: We found the M1b classification to provide clinically relevant information. The multivariate analysis suggested that patients with M1b disease, better performance status and younger age have better survival.

Stereotactic body radiotherapy (SBRT) in recurrent or oligometastatic pancreatic cancer : A toxicity review of simultaneous integrated protection (SIP) versus conventional SBRT.

BACKGROUND: Stereotactic body radiotherapy (SBRT) in pancreatic cancer can be limited by its proximity to organs at risk (OAR). In this analysis, we evaluated the toxicity and efficacy of two different treatment approaches in patients with locally recurrent or oligometastatic pancreatic cancer. MATERIALS AND METHODS: According to the prescription method, patients were divided in two cohorts (C1 and C2). The planning target volume (PTV) was created through a 4 mm expansion of the internal target volume. In C2, a subvolume was additionally created, a simultaneous integrated protection (SIP), which is the overlap of the PTV with the planning risk volume of an OAR to which we prescribed a reduced dose. RESULTS: In all, 18 patients were treated (7 with local recurrences, 9 for oligometastases, 2 for both). Twelve of 23 lesions were treated without SIP (C1) and 11 with SIP (C2). The median follow-up was 12.8 months. Median overall survival (OS) was 13.2 (95% confidence interval [CI] 9.8-14.6) months. The OS rates at 6 and 12 months were 87 and 58%, respectively. Freedom from local progression for combined cohorts at 6 and 12 months was 93 and 67% (95% CI 15-36), respectively. Local control was not statistically different between the two groups. One patient in C2 experienced grade ≥3 acute toxicities and 1 patient in C1 experienced a grade ≥3 late toxicity. CONCLUSION: The SIP approach is a useful prescription method for abdominal SBRT with a favorable toxicity profile which does not compromise local control and overall survival despite dose sacrifices in small subvolumes.

Customized treatment of recurrent gynaecological cancer--the need for intraoperative radiation therapy.

OBJECTIVE: The objective of this retrospective study was to analyze the experience with intraoperative radiation therapy (IORT) at the present institution and to evaluate its contribution to the management of patients with recurrent gynecological cancer. Materials and METHODS: Retrospectively this study reviewed data of patients with a gynecological malignancy considered for treatment with IORT at Freiburg University Medical Center between 2005 and 2012. For this purpose, an analysis of medical records, radiation oncology records, operation reports, and follow-up data was conducted. RESULTS: During the period of this study, 31 women with gynecological cancer underwent tumor resection in combination with IORT. The median age of the patients at the time of IORT was 62 years (range 38-85). Most patients had undergone surgery at the time of initial diagnosis (87%). More than one-third of the patients received prior radiation therapy. In addition to that, 52% of the patients had already received chemotherapy. The majority of patients suffered from the first relapse of their disease. The local recurrence was predominantly located at the pelvic side wall (32%) or in intra-abdominal lymph nodes (32%). In 12 patients the authors did not apply the planned IORT. Intraoperative complications were rare and IORT was tolerated without severe side-effects. Follow-up was 14 months (range 1-65), progression free survival (PFS) was five months (range 3-31). CONCLUSIONS: In carefully selected patients, IORT and cytoreductive surgery contributed to local control and disease palliation. The authors therefore consider IORT an important aspect of modern cancer treatment.

Targeted next-generation sequencing of locally advanced squamous cell carcinomas of the head and neck reveals druggable targets for improving adjuvant chemoradiation.

BACKGROUND: Despite clear differences in clinical presentation and outcome, squamous cell carcinomas of the head and neck (SCCHN) arising from human papilloma virus (HPV) infection or heavy tobacco/alcohol consumption are treated equally. Next-generation sequencing is expected to reveal novel targets for more individualised treatment. PATIENTS AND METHODS: Tumour specimens from 208 patients with locally advanced squamous cell carcinoma of the hypopharynx, oropharynx or oral cavity, all uniformly treated with adjuvant cisplatin-based chemoradiation, were included. A customised panel covering 211 exons from 45 genes frequently altered in SCCHN was used for detection of non-synonymous point and frameshift mutations. Mutations were correlated with HPV status and treatment outcome. RESULTS: Mutational profiles and HPV status were successfully established for 179 cases. HPV- tumours showed an increased frequency of alterations in tumour suppressor genes compared to HPV+ cases (TP53 67% versus 4%, CDKN2A 18% versus 0%). Conversely, HPV+ carcinomas were enriched for activating mutations in driver genes compared to HPV- cases (PIK3CA 30% versus 12%, KRAS 6% versus 1%, and NRAS 4% versus 0%). Hotspot TP53 missense mutations in HPV- carcinomas correlated with an increased risk of locoregional recurrence (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.5-12.1, P=0.006) and death (HR 2.2, 95% CI 1.1-4.4, P=0.021). In HPV+ SCCHN, driver gene mutations were associated per trend with a higher risk of death (HR 3.9, 95% CI 0.7-21.1, P=0.11). CONCLUSIONS: Distinct mutation profiles in HPV- and HPV+ SCCHN identify subgroups with poor outcome after adjuvant chemoradiation. Mutant p53 and the phosphoinositide 3-kinase pathway were identified as potential druggable targets for subgroup-specific treatment optimisation.