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Purpose Perioperative systemic treatment has significantly improved the outcome in locally advanced esophagogastric cancer. However, still the majority of patients relapse and die. Data on the optimal treatment after relapse are limited, and clinical and biological prognostic factors are lacking. Methods Patients with a relapse after neoadjuvant/perioperative treatment and surgery for esophagogastric cancer were analyzed using a prospective database. Applied treatment regimens, clinical prognostic factors and biomarkers were analyzed. Results Of 246 patients 119 relapsed. Among patients with a relapse event, those with an early relapse (p 6 months). OS after relapse was longer in patients with a microsatellite-unstable (MSI) tumor. Systemic treatment was initiated in 87 patients (73% of relapsed pat.); among those OS from the start of first-line treatment was inferior in patients with an early relapse with 6.9 vs. 10.0 months (p = 0.037). In 27 patients (23% of relapsed pat.), local therapy (irradiation or surgical intervention) was performed due to oligometastatic relapse, resulting in a prolonged OS in comparison to patients without local therapy (median OS 35.2 months vs. 7.8 months, p Conclusion Patients relapsing after multimodal treatment have a heterogeneous prognosis depending on the relapse-free interval (if systemic treatment applied), extent of metastatic disease as well as MSI status. The benefit of additional local intervention after relapse should be addressed in a randomized trial.

Purpose The aim of this retrospective analysis is to estimate the most appropriate single cycle and cumulative doses of 225Ac-DOTATOC in patients treated for somatostatin-receptor-expressing cancers. Methods 225Ac-DOTATOC was administered to thirty-nine patients with various somatostatin-receptor-positive tumors. Baseline and follow-up 68Ga-DOTATOC PET/CT, lab tests, and renal scintigraphy were obtained. Patients received long-term follow-up either at the local cancer center or in close collaboration with external oncologists. Acute and chronic hematological toxicity was evaluated quantitatively over time. Long-term follow-up of creatinine was used to approximate the annual loss of estimated GFR (eGFR). Results Dose-dependent acute hematological toxicity was seen at single doses above 40 MBq or repeated doses greater than approximately 20 MBq 225Ac-DOTATOC at 4 month intervals. Treatment-related kidney failure occurred in 2 patients after a delay of >4 years but was independent of administered radioactivity, and other clinical risk factors were important contributors to renal decline. In general, the annual decline of eGFR among patients did not follow a clear dose-effect relationship even in patients with previous β-therapy. An average eGFR-loss of 8.4ml/min (9.9%) per year was observed which is similar to the experience with β-therapy studies. Conclusion Treatment activities of approx. 20 MBq per cycle (4 monthly repetition) and cumulative doses up to 60–80 MBq generally avoided both acute and chronic grade 3/4 hematotoxicity in patients with advanced stage malignancies. Chronic renal toxicity was observed at these doses, but pre-existing renal risk factors were important co-factors. These data represent a starting point for additional research to more precisely define safety thresholds of 225Ac-DOTATOC.

Background Pancreatoblastoma is a rare malignancy that occurs predominantly in children. Less than 50 adult cases, including 17 patients with metastatic disease, have been published to date. Recent outcome data from children with advanced-stage disease suggest an intensive multimodal treatment approach; however, little is known about the most beneficial therapy in adults. Molecular characterization of pancreatoblastoma is limited to a small number of pediatric cases and revealed few recurrent genetic events without immediate clinical relevance. Methods Patients were treated between 2013 and 2018 at a high-volume German university cancer center. Molecular analyses included whole genome, exome, transcriptome, and fusion gene panel sequencing. Molecularly guided treatment recommendations were discussed within a dedicated molecular tumor board (MTB) embedded in a precision oncology program (NCT MASTER). Results We identified four adult patients with metastatic pancreatoblastoma. In three patients, local approaches were combined with systemic treatment. Oxaliplatin-containing protocols showed an acceptable tumor control as well as an adequate toxicity profile. Overall survival was 15, 17, 18 and 24 months, respectively. Three tumors harbored genetic alterations involving the FGFR pathway that included an oncogenic FGFR2 fusion. Conclusion Oxaliplatin-containing chemotherapy seems to be a reasonable approach in adult patients with advanced pancreatoblastoma, whereas the benefit of intensified treatment including local ablative techniques or surgical resection remains unclear. Our finding of FGFR alterations in three of four cases indicates a potential role of FGFR signaling in adult pancreatoblastoma whose clinical significance warrants further study.

Introduction: Thymic epithelial tumors (TETs) are very rare. Thymoma A and AB have a better prognosis than more aggressive thymoma B, thymic carcinoma (TC) and neuroendocrine tumors of the thymus (NET). While previous efforts such as TCGA have mainly characterized thymomas (Radovich et al., Cancer Cell 2018), the molecular landscape of TCs and NETs is still elusive. Patients and Methods: Between 03/2014 and 07/2020, we enrolled 44 TET patients (27 TCs, 11 thymomas, 6 NETs) in a prospective observational study (MASTER) conducted by the National Center for Tumor Diseases (NCT) Heidelberg, NCT Dresden and the German Cancer Consortium (DKTK). MASTER applied whole genome/exome sequencing (WGS, n=22; WES, n=22), transcriptome (n=40) and germline analysis to inform therapy recommendations by a dedicated molecular tumor board (MTB). We systematically gathered follow-up data to evaluate outcome and compared progression-free survival (PFS) of the first treatment according to an MTB recommendation (PFS2) to the last prior systemic treatment (PFS1) in each patient (PFS ratio). Results: Tumor mutational burden (TMB) was low (median=0.99 mutations/Mb, range 0.08-3.48) but higher than in TCGA (p 6 months and a PFS ratio > 1.3. The best outcome was achieved using imatinib in a patient with a KIT mutation (p.W557R). After progression, the MTB recommended ponatinib based on a secondary KIT mutation (p.V654A). The patient was still on ponatinib when the observation period ended. Conclusion: We demonstrate that comprehensive molecular analysis provides clinically relevant information in a subgroup of TET patients. Thymoma, TCs, and NETs present with different molecular characteristics. Distinction between immunologically hot and cold TCs may have value for risk stratification and therapeutic strategies. PARP inhibition could be a potential new treatment option in a small subgroup of TETs. Molecular testing of KIT, germline analysis and genetic counseling should be recommended for all patients with advanced TETs. Citation Format: Lino Möhrmann, Lysann Rostock, Małgorzata Oleś, Arne Jahn, Marie Arlt, Nagarajan Paramasivam, Korinna Jöhrens, Luise Rupp, Marc Schmitz, Daniela Richter, Sebastian Uhrig, Martina Fröhlich, Barbara Hutter, Jennifer Hüllein, Elena E. Wolf, Dorothea Hanf, Laura Gieldon, Simon Kreutzfeldt, Christoph E. Heilig, Veronica Teleanu, Daniel B. Lipka, Andreas Mock, Ivan Jelas, Damian T. Rieke, Marcel Wiesweg, Melanie Boerries, Anna L. Illert, Alexander Desuki, Thomas Kindler, Angela M. Krackhardt, C. Benedikt Westphalen, Heidrun Grosch, Leonidas Apostolidis, Albrecht Stenzinger, Irina A. Kerle, Christoph Heining, Daniel Hübschmann, Evelin Schröck, Stefan Fröhling, Hanno Glimm. Genomics-based personalized oncology of advanced thymic epithelial tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 926.

PD-1/PD-L1 inhibitors do not show activity in mismatch repair proficient (MMRp) colorectal cancer. Inhibition of C-C motif chemokine receptor 5 (CCR5) leads to an antitumoral activation of macrophages, affecting immune cell infiltrates. PICCASSO is a phase I trial exploring safety and efficacy of pembrolizumab and maraviroc in refractory MMRp CRC.Twenty patients received pembrolizumab and maraviroc (core period, eight cycles), followed by pembrolizumab monotherapy. Primary endpoint was the feasibility rate (patients without treatment-related grade ≥3 immune-related adverse events, treatment-related grade ≥4 adverse events, or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). Optional biopsies of liver metastases were performed for analyses of the micromilieu.The feasibility rate was 94.7% [90% CI 77.4-99.7%], with one grade 4 hyperglycemia and no additional ≥ grade 3 treatment-related toxicities. ORR according to RECIST was 5.3%. Median PFS according to RECIST was 2.10 months [95%CI 1.68-2.30], median OS 9.83 months [95% CI, 5.59-20.02]. Disease control rate of poststudy salvage treatment was70%. Translational analyses showed an increase of antitumoral chemokines during treatment; eotaxin, a chemokine involved in chemotaxis, was identified as a biomarker linked to OS.Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MMRp CRC patients was limited with prolonged disease stabilizations observed in single patients. Efficacy of poststudy salvage treatment and OS was higher than expected in this heavily pretreated population. THIS TRIAL IS REGISTERED AT CLINICALTRIALS.GOV: NCT03274804.

The multi-receptor tyrosine kinase inhibitor pazopanib is approved for the treatment of advanced soft-tissue sarcoma and has also shown activity in other sarcoma subtypes. However, its clinical efficacy is highly variable, and no reliable predictors exist to select patients who are likely to benefit from this drug.We analysed the molecular profiles and clinical outcomes of patients with pazopanib-treated sarcoma enrolled in a prospective observational study by the German Cancer Consortium, DKTK MASTER, that employs whole-genome/exome sequencing and transcriptome sequencing to inform the care of young adults with advanced cancer across histology and patients with rare cancers.Among 109 patients with available whole-genome/exome sequencing data, there was no correlation between clinical parameters, specific genetic alterations or mutational signatures and clinical outcome. In contrast, the analysis of a subcohort of 62 patients who underwent molecular analysis before pazopanib treatment and had transcriptome sequencing data available showed that mRNA levels of NTRK3 (hazard ratio [HR] = 0.53, p = 0.021), IGF1R (HR = 1.82, p = 0.027) and KDR (HR = 0.50, p = 0.011) were independently associated with progression-free survival (PFS). Based on the expression of these receptor tyrosine kinase genes, i.e. the features NTRK3-high, IGF1R-low and KDR-high, we developed a pazopanib efficacy predictor that stratified patients into three groups with significantly different PFS (p lt; 0.0001). Application of the pazopanib efficacy predictor to an independent cohort of patients with pazopanib-treated sarcoma from DKTK MASTER (n = 43) confirmed its potential to separate patient groups with significantly different PFS (p = 0.02), whereas no such association was observed in patients with sarcoma from DKTK MASTER (n = 97) or The Cancer Genome Atlas sarcoma cohort (n = 256) who were not treated with pazopanib.A score based on the combined expression of NTRK3, IGF1R and KDR allows the identification of patients with sarcoma and with good, intermediate and poor outcome following pazopanib therapy and warrants prospective investigation as a predictive tool to optimise the use of this drug in the clinic.

Patients with cancer frequently receive immune-checkpoint inhibitors (ICIs), which may modulate immune responses to COVID-19 vaccines. Recently, cytokine release syndrome (CRS) was observed in a patient with cancer who received BTN162b2 vaccination under ICI treatment. Here, we analyzed adverse events and serum cytokines in patients with 23 different tumors undergoing (n = 64) or not undergoing (n = 26) COVID-19 vaccination under ICI therapy in a prospectively planned German single-center cohort study (n = 220). We did not observe clinically relevant CRS (≥grade 2) after vaccination (95% CI 0-5.6%; Common Terminology of Adverse Events v.5.0) in this small cohort. Within 4 weeks after vaccination, serious adverse events occurred in eight patients (12.5% 95% CI 5.6-23%): six patients were hospitalized due to events common under cancer therapy including immune related adverse events and two patients died due to conditions present before vaccination. Despite absence of CRS symptoms, a set of pairwise-correlated CRS-associated cytokines, including CXCL8 and interleukin-6 was1.5-fold upregulated in 40% (95% CI 23.9-57.9%) of patients after vaccination. Hence, elevated cytokine levels are common and not sufficient to establish CRS diagnosis.

Purpose Magnetic resonance neurography (MRN) can detect dorsal root ganglia (DRG) hypertrophy in patients with oxaliplatin-induced peripheral neuropathy (OXIPN) but is difficult to apply in clinical daily practice. Aims of this study were (i) to assess whether DRG volume is reliably measurable by routine computed tomography (CT) scans, (ii) to measure longitudinal changes in DRG during and after oxaliplatin administration and (iii) to assess correlation between DRG morphometry and individual oxaliplatin dose. Methods For comparison of MRN and CT measurements, CT scans of 18 patients from a previous MRN study were analyzed. For longitudinal assessment of DRG size under treatment, 96 patients treated with oxaliplatin between January and December 2014 were enrolled retrospectively. DRG volumetry was performed by analyzing routine CT scans, starting with the last scan before oxaliplatin exposure (t0) and up to four consecutive timepoints after initiation of oxaliplatin therapy (t1–t4) with the following median and ranges in months: 3.1 (0.4–4.9), 6.2 (5.3–7.8), 10.4 (8.2–11.9), and 18.4 (12.8–49.8). Results DRG volume measured in CT showed a moderately strong correlation with MRN (r = 0.51, p p t2. Higher cumulative oxaliplatin exposure was associated with significantly higher absolute DRG volumes (p = 0.005). Treatment discontinuation was associated with a nonsignificant trend towards lower relative DRG volume changes (p = 0.08). Conclusion CT is a reliable method for continuous DRG morphometry; however, since no standardized assessment of OXIPN was performed in this retrospective study, correlations between DRG size, cumulative oxaliplatin dose and clinical symptoms in future prospective studies are needed to establish DRG size as a potential OXIPN biomarker.

Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE (n = 37), 56.4% for FOLFOX (n = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) (n = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) (n = 20), and 16.7% for other (n = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX (p = 0.333), 12.0 months for TEM/CAP (p = 0.093), 4.8 months for STZ/5-FU (p = 0.919), and 14.1 months for other (p = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months, p = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed.

Background Cytotoxic chemotherapy combinations and targeted agents represent established treatment concepts in advanced pancreatic neuroendocrine tumors (PNETs). However, response rates, side effects and outcome data strongly vary among these therapeutic approaches. Head-to-head comparisons between chemo- and molecular therapies are missing and secondary resistances frequently occur. The RamuNET trial aims to identify the effectiveness of dual treatment with DTIC and ramucirumab in progressive advanced PNET patients. Methods The RamuNET study is an investigator-initiated multicenter prospective single-arm trial to evaluate the efficacy of ramucirumab in combination with dacarbazine (DTIC) over a period of at least 6 months. Patients with progressive well-differentiated and metastatic pancreatic neuroendocrine tumors are eligible. The study aims to include 45 patients over a period of 24 months with a minimum follow-up of 24 months. The primary endpoint is disease control after 6 months. Secondary endpoints include progression-free survival, biochemical response, overall survival, quality of life and toxicity. Based on the hypothesis that 80% of the patients can achieve a disease control after 6 months, the sample size calculation follows an exact binomial single-stage design. H0: p =p1 = 80%, alpha = 0.05, beta = 0.1. Discussion This study investigates a new therapeutic approach using the combination of cytotoxic and targeted antiangiogenic therapy in advanced PNET. If positive, this trial will be the basis for a randomized two-arm study to investigate the combination of ramucirumab and DTIC against other established therapies in PNET. Trial registration EudraCT: 2017–001207-68 . Date of registration: 2018.01.03.

PurposeThe main aim of the study was to explore the expectations and knowledge of advanced-stage cancer patients about immunotherapy.MethodsThis mixed methods study included 53 cancer patients on immune checkpoint inhibitors (ICIs), 55 cancer patients undergoing chemotherapy (CT), and 53 non-cancer patients. Participants’ expectations about ICIs and CT were compared. Additional qualitative data were derived from semi-structured interviews.ResultsAmong patients who did not receive ICIs, 63 (58%) had never heard of ICIs and 94 (87%) had large gaps in their knowledge of ICIs. Among ICI patients, 33 (62%) simply described ICIs without errors. ICI perception was positive, regardless of whether respondents received or had heard of ICIs, which became particularly evident when compared to CT. ICIs were rated as more promising, and all adverse effects were expected to be significantly lower than those of CT. Knowledge about ICIs was also limited in the interviewed ICI patients. Some patients reported adverse effects of ICIs that were mostly mild and well-tolerated or easily treated.ConclusionsThe lack of understanding of ICIs should be improved by activities to increase the knowledge of ICI patients and the general population. In contrast to CT, ICIs invoked fewer negative associations with efficacy and toxicity. Therefore, attention should be paid to risk awareness when educating patients. (Clinical trial registration number: DRKS00011868)Trial Registration: German clinical trials register,www.germanctr.de, number DRKS00011868.

Perioperative systemic treatment is standard of care for Caucasian patients with locally advanced, resectable gastric adenocarcinoma. The prognostic relevance of the microsatellite instability (MSI) status in patients undergoing neoadjuvant chemotherapy followed by resection is unclear. We analyzed the association of the MSI status with histological regression and clinical outcome in patients undergoing neoadjuvant systemic treatment. Tumor tissue from patients undergoing neoadjuvant chemotherapy followed by resection for gastric or gastroesophageal-junction adenocarcinoma was analyzed for MSI status using a mononucleotide marker panel encompassing the markers BAT25, BAT26, and CAT25. Histological regression, relapse-free survival and overall survival were calculated and correlated with MSI status. We identified the MSI-H phenotype in 9 (8.9%) out of 101 analyzed tumors. Though a poor histological response was observed in eight out of nine MSI-H patients, overall survival was significantly better for patients with MSI-H compared to MSS tumors (median overall survival not reached vs. 38.6 months, log-rank test p = 0.014). Among MSI-H patients, an unexpected long-term survival after relapse was observed. Our data indicate that the MSI-H phenotype is a favorable prognostic marker in gastric cancer patients undergoing neoadjuvant treatment. The benefit of perioperative cytotoxic treatment in patients with MSI-H gastric cancer, however, remains questionable. Future trials should stratify patients according to their MSI status, and novel treatment modalities focusing on MSI-H tumors should be considered.

// Leonidas Apostolidis 1 , Cathleen Nientiedt 1 , Eva Caroline Winkler 1 , Anne Katrin Berger 1 , Clemens Kratochwil 2 , Annette Kaiser 3 , Anne-Sophie Becker 3 , Dirk Jager 1 , Markus Hohenfellner 4 , Clemens Huttenbrink 5 , Sascha Pahernik 5 , Florian A. Distler 5, * and Carsten Grullich 1, * 1 Department of Medical Oncology, National Center for Tumor Diseases, University Hospital Heidelberg, Heidelberg, Germany 2 Department of Nuclear Medicine, University Hospital Heidelberg, Heidelberg, Germany 3 Institute of Pathology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany 4 Department of Urology, University Hospital Heidelberg, Heidelberg, Germany 5 Department of Urology, Klinikum Nuremberg, Paracelsus Medical University, Nuremberg, Germany * These authors have contributed equally to this work Correspondence to: Leonidas Apostolidis, email: leonidas.apostolidis@med.uni-heidelberg.de Keywords: neuroendocrine carcinoma; neuroendocrine tumor; carcinoid; prostate; chemotherapy Received: September 19, 2018 Accepted: December 10, 2018 Published: January 01, 2019 ABSTRACT Background: Neuroendocrine carcinomas of the prostate (NEPCs) are rare tumors with poor prognosis. While platinum and etoposide-based chemotherapy regimens (PE) are commonly applied in first-line for advanced disease, evidence for second-line therapy and beyond is very limited. Methods: Retrospective analysis of all patients with NEPCs including mixed differentiation with adenocarcinoma component and well differentiated neuroendocrine tumors (NETs, carcinoids) at two high-volume oncological centers between 12/2000 and 11/2017. Results: Of 46 identified patients 39.1 % had a prior diagnosis of prostatic adenocarcinoma only, 43.5 % had a mixed differentiation at NEPC diagnosis, 67.4 % developed visceral metastases, 10.9 % showed paraneoplastic syndromes. Overall survival (OS) from NEPC diagnosis was 15.5 months, and significantly shorter in patients with a prior prostatic adenocarcinoma (5.4 vs. 32.7 months, p=0.005). 34 patients received palliative first-line systemic therapy with a median progression-free survival (PFS) of 6.6 months, mostly PE. Overall response rate (ORR) for PE was 48.1 %. 19 patients received second-line therapy, mostly with poor responses. Active regimens were topotecan (1 PR, 3 PD), enzalutamide (1 SD), abiraterone (1 SD), FOLFIRI (1 SD), and ipilimumab+nivolumab (1 PR). One patient with prostatic carcinoid was sequentially treated with octreotide, peptide receptor radionuclide therapy and everolimus, and survived for over 9 years. Conclusions: EP in first-line shows notable ORR, however limited PFS. For second-line therapy, topotecan, FOLFIRI, enzalutamide, abiraterone and immune checkpoint blockade are treatment options. Prostatic carcinoids can be treated in analogy to well differentiated gastrointestinal NETs.

Background To assess the predictive value of early metabolic response (ΔSUV) after short-term treatment with first-line cetuximab in patients (pts) with RAS-wt metastatic colorectal cancer (mCRC). Methods In this prospective phase II study, RAS-wt mCRC pts received a single-agent cetuximab run-in therapy of 2 weeks. ΔSUV was assessed with FDG-PET/CT on days 0 and 14. Early clinical response (ECR) was evaluated with CT on day 56 after treatment with FOLFIRI-cetuximab. Primary endpoint was the predictive significance of ΔSUV for ECR. Secondary endpoints were PFS (progression free survival), OS and the influence of ΔSUV on survival. Results Forty pts were enroled and 33 pts were evaluable for the primary endpoint. The CT response rate was 57.6%. For responders, ΔSUV was significantly higher (p = 0.0092). A significant association of ΔSUV with ECR was found (p = 0.02). Median PFS was 11.7 months and median OS was 33.5 months with a 1-year survival rate of 87.9%. ΔSUV was found to significantly impact the hazard for OS (p = 0.045). Conclusions We demonstrate that cetuximab induces metabolic responses in mCRC pts. The study endpoint was met with the ΔSUV discriminating between responders and non-responders. However, these data should be validated in larger patient cohorts.

Background/Aim: Sorafenib leads to improved survival in advanced hepatocellular carcinoma (HCC) patients. Continuation of sorafenib beyond progression has been a possible treatment strategy when further approved therapeutic agents are lacking. Methods: We performed a retrospective analysis of all HCC patients at our institution with documented disease progression under treatment with sorafenib. Overall survival (OS) from start of sorafenib treatment was compared between patients who received sorafenib for > 3 weeks beyond progression (group 1) and those who discontinued sorafenib ≤3 weeks after progression (group 2). Group 1 was further subdivided into those patients who received sorafenib for > 3 months (group 1a) and those who received it for ≤3 months (group 1b). Results: A total of 71 patients were analyzed. Median OS for all patients was 15.4 months. OS in group 1 (15.6 months) and 2 (13.0 months) was similar (p = 0.90). Patients in group 1a showed significantly prolonged median OS (19.7 months) compared to that of patients in group 1b (13.6 months, p = 0.004), and they showed a trend towards prolonged OS compared to group 2 (p = 0.126). For patients with a poor prognosis according to their Child-Pugh stage, performance status, alpha-fetoprotein, and response to prior sorafenib treatment, OS was significantly prolonged in group 1 versus group 2 (12.1 vs. 6.4 months, p = 0.019). Conclusion: In HCC patients, continuing sorafenib beyond progression for > 3 months is associated with improved survival compared to discontinuing sorafenib within 3 months. Furthermore, patients with a poor prognosis who continue sorafenib beyond progression in general show significantly prolonged survival.

Background Defects in DNA damage repair genes characterize a subset of men with prostate cancer and provide an attractive opportunity for precision oncology approaches. The prevalence of such perturbations in newly diagnosed, treatment-naive patients with a high risk for lethal disease outcome, however, has not been sufficiently explored. Patients and Methods Prostate cancer specimens from 67 men with newly diagnosed early onset, localized high-risk/locally advanced or metastatic prostate cancer were included in this prospective pilot study. Tumor samples, including 30 prostate biopsies, were analyzed by targeted next generation sequencing using a formalin-fixed, paraffin-embedded tissue-optimized 37 DNA damage repair and checkpoint gene panel. Results The drop-out rate due to an insufficient quantity of DNA was 4.5% (3 of 67 patients). In the remaining 64 patients, the rate of pathogenic DNA damage repair gene mutations was 26.6%. The highest rate of pathogenic DNA damage repair and checkpoint gene mutations was found in men with treatment-naive metastatic prostate cancer (38.9%). In addition, a high number of likely pathogenic mutations and gene deletions were detected. Altogether, one or more pathogenic mutation, likely pathogenic mutation or gene deletion affected 43 of 64 patients (67.2%) including 29 of 36 patients (80.6%) with treatment-naive metastatic prostate cancer. Men with metastatic prostate cancer showed a high prevalence of alterations in TP53 (36.1%). Conclusions This pilot study demonstrates the feasibility, performance and clinical relevance of somatic targeted next generation sequencing using a unique 37 DNA damage repair and checkpoint gene panel under routine conditions. Our results indicate that this approach can detect actionable DNA repair gene alterations, uncommon mutations as well as mutations associated with therapy resistance in a high number of patients, in particular patients with treatment-naive metastatic prostate cancer.

4607 Background: Well differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications from 2017 and 2019. Retrospective data suggest that commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Therefore, current treatment guidelines suggest alternative first-line treatment protocols like temozolomide-based (TEM), streptozotocin-based (STZ) and FOLFOX which have only been studied in second-line so far. The aim of this multicenter analysis was to evaluate treatment outcomes for NET G3 with a focus on the efficacy of different first-line regimens. Methods: We performed retrospective analysis of all patients with NET G3 in the NEN databases of 3 German cancer centers. All histopathological findings were reviewed by the investigators in order to comply with the most current WHO classification. Results: A total of 131 patients could be identified. Median Ki67 was 30 %, primary tumors were located in the pancreas in 71 % of cases, 20 patients had a history of prior NET G1/G2 diagnosis. Median overall survival (OS) was 138.1 months with a median follow-up of 20.4 months. 125 patients received palliative first-line therapy: PE n = 34, FOLFOX n = 36, TEM (mostly temozolomide+capecitabine) n = 21, STZ n = 19, other (including targeted agents, somatostatin analogues, PRRT and multimodal combination approaches) n = 15. Overall response (ORR) and disease control rate was 35.3 % and 67.6 % for PE, 52.8 % and 80.6 % for FOLFOX, 28.6 % and 66.7 % for TEM, 47.4 % and 68.4 % for STZ, 20.0 % and 73.3 % for other respectively. Median progression-free survival for PE was 5.2 months. Compared to PE, PFS in the other treatment groups was 6.0 months for FOLFOX (p = 0.164), 12.0 months for TEM (p = 0.059), 5.7 months for STZ (p = 0.519), 14.1 months for other (p = 0.003). All non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 vs. 5.2 months; p = 0.011). 89 patients received second-line systemic therapy with a median PFS of 5.3 months. Conclusions: In this first multicenter analysis of different treatment strategies for NET G3, patients receiving upfront treatment with non-PE regimens had a significantly prolonged PFS. Of the single defined protocols, FOLFOX showed the highest ORR, and TEM the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this newly defined tumor entity is needed.

3010 Background: Checkpoint inhibition using PD-1/PD-L1 inhibitors does not show clinically relevant activity in MSS/pMMR (Mismatch Repair Proficient) colorectal cancer. Previous work showed that inhibition of CCR5 (C-C chemokine receptor type 5) leads to a macrophage re-polarization towards M1 macrophages within the tumor microenvironment which directly affects immune cell infiltrates. The current phase I trial explores a combined modification of the innate immune system (by CCR 5 blockade) and the adaptive immune system (by PD-1 inhibition) in the treatment of MSS CRC. Methods: 20 patients with metastatic MSS/pMMR colorectal cancer with failure of fluoropyrimidines, oxaliplatin, irinotecan, VEGF antibodies and EGFR antibodies (in ras WT patients) received pembrolizumab 200 mg q21d and maraviroc 300 mg bid cont. for 8 cycles, followed by pembrolizumab monotherapy for a maximum of 24 additional cycles. Imaging was performed every nine weeks (RECIST and irRECIST criteria). Primary endpoint was the feasibility rate (rate of patients receiving the protocol treatment during the core treatment without special event: treatment-related Grade ≥ 3 immune-related abnormalities, treatment-related Grade ≥ 4 AEs or any toxicity-related premature withdrawal of treatment). Secondary endpoints included safety/toxicity, ORR, PFS and OS. Results: 20 patients were enrolled. The median number of applied cycles was 3.5 for pembrolizumab and 3.5 for maraviroc. Two patients completed the core treatment period with pembrolizumab and started maintenance treatment. The feasibility rate was 94.7% (90% CI 77.4 to 99.7%), with one patient experiencing a special event. Except this grade 4 event (hyperglycemia) no ≥ 3 treatment-related toxicities were observed. According to irRECIST criteria one patient showed a partial response and one a stable disease as best response, resulting in an irDCR of 10.5%. Median PFS according to irRECIST was 2 months (CI 95%, 2 to 3), median OS 9 months (CI 95%, 6 to 20). Conclusions: Therapy with pembrolizumab and maraviroc was feasible and showed a beneficial toxicity pattern. Clinical activity in MSS CRC patients was limited, however prolonged disease stabilizations were observed in single patients and overall survival was higher than expected in this heavily pretreated population. Clinical trial information: NCT03274804 .

6533Background: Financial toxicity of cancer has so far been discussed primarily in the US health care system and has been shown to be associated with higher morbidity and mortality. In Germany wit...

Background Therapeutic options for neuroendocrine neoplasms (NEN) are limited, and only few NEN patients have been treated according to their individual genomic profile. We report the molecular and clinical characteristics of a large NEN cohort that was studied by prospective whole-genome (WGS), whole-exome (WES), and transcriptome sequencing (TS) within the NCT/DKTK MASTER precision oncology program. Methods Between 2013 and 2018, a total of 115 patients with advanced, heavily pretreated NEN were enrolled. Primary sites were gastrointestinal (n = 30), pancreatic/hepatic (n = 33), pulmonary (n = 20), genitourinary (n = 13), head/neck (n = 6), and other regions (n = 11). Grading according to the 2017 and 2019 WHO classification was neuroendocrine tumor (NET) G1, n = 12; NET G2, n = 31; NET G3, n = 12; neuroendocrine carcinoma, n = 36; mixed neuroendocrine-non-neuroendocrine neoplasm, n = 12; and other, n = 11. Results Of WES (n = 72) or WGS (n = 44) and TS (n = 92) were discussed in a multidisciplinary molecular tumor board. Recommendations were given in 103 cases (94%) for the following potential treatment alternatives: tyrosine or serine/threonine kinase inhibition (n = 67), PARP inhibition (n = 41), immunotherapy (n = 33), mTOR inhibition (n = 30), CDK4/6 inhibition (n = 19), MEK inhibition (n = 12), platinum-based chemotherapy (n = 7), BET inhibition (n = 7), anti-claudin18.2 (n = 5) or anti-DLL3 antibody treatment (n = 8). Somatic hypermutation (>10 mutations/megabase) was seen in 8.6% of patients. Treatment options could be implemented in 35 patients, of which 31 were evaluable for response: partial response, n = 10; mixed response, n = 1; stable disease, n = 11; progressive disease, n = 9; resulting in an overall response rate of 32% and a disease control rate of 71%. Conclusions Comprehensive genomic and transcriptomic characterization provides new insight into the molecular pathogenesis of NEN and creates therapeutic opportunities in a significant proportion of NEN patients who have exhausted standard treatment. Legal entity responsible for the study NCT Heidelberg & German Cancer Consortium. Funding German Cancer Research Center. Disclosure S. Kreutzfeldt: Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self): Novartis; Research grant / Funding (institution): Roche; Travel / Accommodation / Expenses: Pfizer. C.E. Heilig: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (institution), Travel / Accommodation / Expenses: Lilly; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: Celgene; Travel / Accommodation / Expenses: Teva; Travel / Accommodation / Expenses: BMS; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): Pfizer. All other authors have declared no conflicts of interest.

Background Therapeutic options for metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma (EPNEC) after prior platinum-based chemotherapy are limited. Combination chemotherapy protocols with cyclophosphamide, vincristine and either doxorubicin/adriamycin (CAV) or epirubicin (CEV) are possible treatment options for small cell lung cancer (SCLC), however have not been systematically evaluated in EPNEC so far. The aim of this study was to analyze the efficacy and toxicity of CAV/CEV in metastatic EPNEC patients. Methods We reviewed the combined prospective and retrospective NEN database of our center for patients treated with CAV or CEV between January 2009 and January 2019. Histological findings of all patients were reevaluated by the investigators in order to comply with the most current WHO classification. Results A total of 22 patients could be identified, 19 received CAV, 3 CEV. Patients had been treated with a median of 1 line of prior chemotherapy. Median proliferation rate (Ki67) was 70 %, small cell histology was present in 63.6 % of cases. Primaries were gastrointestinal (27.3 %), pancreatobiliary (22.7%), urogenital (22.7 %), head/neck (9.1 %) or unknown (18.2 %). Best response to CAV/CEV was stable disease in 3 patients, partial remission (PR) in 5, resulting in an overall response rate of 22.7 % and disease control rate of 36.4 %. Most notably, PR was observed in both 2 patients included with a prostatic primary. Of the remaining 14 patients, 12 (54.5 %) showed a progressive disease, 1 showed a mixed response and 1 was not evaluable for response. Median progression free (PFS) and overall survival (OS) after start of CAV/CEV was 2.0 and 10.0 months respectively. Significant toxicity (mainly hematotoxicity) was observed in 63.6 % of patients. Conclusions In this first analysis of CAV/CEV in EPNEC so far, moderate antitumor activity could be detected, most notably in patients with a prostatic primary. Despite some encouraging responses, PFS was limited and significant toxicities were observed in the majority of patients. Clinical trial identification The trial was approved by the institutional research ethics committee (approval S-428/2014). Legal entity responsible for the study National Center for Tumor Diseases (NCT) Heidelberg. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.

Therapeutic options for neuroendocrine neoplasms (NEN) are limited. Within the MASTER program, a multi-institutional registry trial for prospective stratification of younger adults with advanced-stage cancer across all histologies and patients with rare tumors conducted under the auspices of NCT Heidelberg/Dresden and the German Cancer Consortium, we apply prospective whole-exome/genome sequencing (WES/WGS) and RNA sequencing (RNA-seq) to determine therapeutic choices for individual patients who have exhausted standard therapy options. We here report the clinical and molecular characteristics of the NEN cohort within this study. Between 2013 and 2018, 108 patients (male, n=65; female, n=43) were enrolled. Histologies according to the 2017 WHO Classification were neuroendocrine tumor grade 1 (NET G1), n=8; NET G2, n=31; NET G3, n=9; neuroendocrine carcinoma, n=49; and mixed neuroendocrine/non-neuroendocrine neoplasm, n=11. Primary tumor sites were gastrointestinal tract, n=30; pancreas, n=31; thorax, n=21; genitourinary system, n=11; head and neck, n=5; and other regions, n=10. All patients had advanced-stage disease and had received a median of 2 prior lines of systemic therapy. WES, WGS, and RNA-seq were performed in 69, 40, and 87 patients, respectively. Clinical evaluation of germline and somatic molecular data (single-nucleotide variants, small insertions and deletions, copy number variations, mutational burden, mutational signatures, homologous recombination deficiency scores, gene expression patterns, etc.) from 105 patients by a dedicated molecular tumor board yielded evidence-based recommendations for clinical management in 91 cases (87%). Treatment recommendations were grouped as follows: PARP inhibition, n=35; immunotherapy, n=27; mTOR inhibition, n=22; CDK4/6 inhibition, n=15; tyrosine or serine/threonine kinase inhibition, n=57 (ALK, n=1; ERBB, n=6; FGFR, n=10; MET, n=5; RET, n=12; VEGFR, n=4, MEK, n=9; other, n=10), DNA-crosslinking chemotherapy, n=16; anti-claudin18.2 antibody, n=5; BET inhibition, n=5; and DLL3 antibody, n=5. As of November 2018, at least 18 patients had received molecularly guided treatment (PARP inhibition, immunotherapy, mTOR inhibition, tyrosine or serine/threonine kinase inhibition) of which 11 were evaluable for response (partial response, n=4; stable disease, n=2; progressive diseases, n=5). Twenty-seven patients died before therapy could be started, 16 are currently receiving other regimens, and for the remaining patients no follow-up data are available yet. In conclusion, comprehensive molecular profiling offers valuable insight into to the genomic and transcriptomic landscape of NEN and creates additional therapeutic opportunities in a subset of patients. Citation Format: Simon Kreutzfeldt, Leonidas Apostolidis, Malgorzata Oles, Peter Horak, Christoph E. Heilig, Christoph Heining, Barbara Hutter, Laura Gieldon, Barbara Klink, Mario Lamping, Damian T. Rieke, Sebastian Uhrig, Henning Jann, Ulrich F. Pape, Albrecht Stenzinger, Eva C. Winkler, Bertram Wiedenmann, Dirk Jäger, Benedikt Brors, Evelin Schröck, Ulrich Keilholz, Marianne Pavel, Hanno Glimm, Stefan Fröhling. Clinical relevance of comprehensive genomic analysis in patients with advanced-stage neuroendocrine neoplasms: Results from the MASTER trial of the German Cancer Consortium [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 919.

4103 Background: High grade Neuroendocrine Neoplasias (NEN) are rare tumors with a poor prognosis and no established second line therapy when progressive after first line platinum-based chemotherapy resulting in a median overall survival (OS) of 5 months. This study aims to evaluate the efficacy and safety of the anti-programmed death ligand-1 (PD-L1) antibody Avelumab in patients (pts) with NEN G3 progressing after first-line chemotherapy. Methods: In a multicenter, national, single-arm, open-label, phase II trial the efficacy and safety of Avelumab was evaluated in patients with metastatic progressive Neuroendocrine Carcinomas (NEC G3) according to WHO 2010, excluding Merkel cell carcinoma and small cell lung cancer. Results: From 12/2017-11/2018 a total of 29 pts (20 male, 69%), were enrolled (16 NEC G3 and 11 moderately differentiated NETG3). Mean age was 59.2±10.2 ys (range 33-75), median follow up 16.5 weeks (3-48). Median Ki67 was 60% (range 20-95%). Site of origin included pancreas (12), genito-urinary tract (4), stomach-esophagus (3), colo-rectum (3), lung (2), ear-nose-throat (2), papilla of Vater (1). In an interim analysis the DCR (stable disease or partial remission according to irRECIST) after 8 weeks was 32% (4 SD, 2 PR). In responders, mean duration of disease control was 20 (±13.8) weeks, with 4 pts. showing stable disease or partial remission ≥6 months. Median OS was 4.2 months (range 1- >12). Treatment-related adverse events occurred in 11 of 29 pts (38%) and were mainly mild to moderate (CTCAE-grade 1 [52%], 2 [44%] and 3 [4%]) and included fatigue (n=6; 20.6%), diarrhea (n=4; 13.7%), fever/chills after infusion (n=4; 13.7%), loss of appetite and nausea (n=4; 13.7%), skin rash (n=1; 3%), deterioration of preexisting psoriasis (n=1; 3%) and abdominal pain (n=1; 3%). Conclusions: Immune checkpoint blockade with avelumab in pretreated high grade NEN shows relevant activity in a subset of patients with excellent tolerability. Clinical trial information: NCT03352934.

Purpose To investigate in vivo morphological and functional correlates of oxaliplatin-induced peripheral neuropathy (OXA-PNP) by magnetic resonance neurography (MRN). Methods Twenty patients (7 female, 13 male, 58.9±10.0 years) with mild to moderate OXA-PNP and 20 matched controls (8 female, 12 male, 55.7±15.6 years) were prospectively enrolled. All patients underwent a detailed neurophysiological examination prior to neuroimaging. A standardized imaging protocol at 3.0 Tesla included the lumbosacral plexus and both sciatic nerves and their branches using T2-weighted fat-saturated sequences and diffusion tensor imaging. Quantitative assessment included volumetry of the dorsal root ganglia (DRG), sciatic nerve normalized T2 (nT2) signal and caliber, and fractional anisotropy (FA), mean diffusivity (MD), axial (AD) and radial diffusivity (RD). Additional qualitative evaluation of sciatic, peroneal, and tibial nerves evaluated the presence, degree, and distribution of nerve lesions. Results DRG hypertrophy in OXA-PNP patients (207.3±47.7mm3 vs. 153.0±47.1mm3 in controls, p = 0.001) was found as significant morphological correlate of the sensory neuronopathy. In contrast, peripheral nerves only exhibited minor morphological alterations qualitatively. Quantitatively, sciatic nerve caliber (27.3±6.7mm2 vs. 27.4±7.4mm2, p = 0.80) and nT2 signal were not significantly changed in patients (1.32±0.22 vs. 1.22±0.26, p = 0.16). AD, RD, and MD showed a non-significant decrease in patients, while FA was unchanged. Conclusion OXA-PNP manifests with morphological and functional correlates that can be detected in vivo by MRN. We report hypertrophy of the DRG that stands in contrast to experimental and postmortem studies. DRG volume should be further investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies.

e16163Background: Mixed neuroendocrine-nonneuroendocrine neoplasms (MiNEN) have been newly defined in the WHO 2017 classification of tumors of the endocrine organs. They are considered rare and are...

Hepatocellular carcinoma (HCC) is one of the most common tumor diseases worldwide. Dermatomyositis is a known paraneoplastic syndrome that can complicate the course of a variety of different cancers, however, the association with HCC is extremely rare.Here, we report on a patient with the rare concurrence of dermatomyositis and non-hepatitis-associated advanced HCC with intra-abdominal and intrathoracal lymph node metastases. The HCC was treated with sorafenib. The dermatomyositis responded well to treatment with prednisolone and azathioprin although sorafenib did not lead to a response in the underlying HCC.Paraneoplastic dermatomyositis can be associated with non-hepatitis-associated HCC. The potential pathogenetic links between these two diseases are discussed, as well as a potential immunomodulatory effect of sorafenib independent of its antineoplastic potential.

Therapeutic options for metastatic poorly differentiated neuroendocrine carcinoma (NEC) after prior platinum‐based chemotherapy are limited. Topotecan is an approved second‐line chemotherapy for small cell lung cancer (SCLC). NEC is often considered to show a biological behavior similar to SCLC. The aim of this study was to analyze the efficacy of topotecan in pretreated metastatic NEC patients. We performed a retrospective analysis of all patients treated with topotecan for metastatic NEC who presented at our center between January 2005 and December 2014 (n = 30). All 30 patients had received at least a platinum and etoposide containing regimen as prior chemotherapy. Median proliferation rate (Ki67) was 80%. As best response to topotecan five patients showed a stable disease, two patients a partial remission, resulting in a disease control rate of 23%. Of the remaining 23 patients, 14 (47%) showed a progressive disease, nine (30%) died before radiologic response could be evaluated. Median progression‐free (PFS) and overall survival (OS) after start of topotecan was 2.1 and 4.1 months, respectively. In the subgroup analysis, patients with unknown primary (vs. those with a known primary) showed a significantly prolonged PFS of 3.5 months (vs. 1.9, P = 0.0107) and OS of 6.7 months (vs. 2.6 months, P = 0.0168). Grade 3/4 hematotoxicity was observed in 60% of patients. Topotecan shows only moderate antitumor activity in metastatic NEC. Disease control rate is lower than reported for SCLC. However, antitumor activity of topotecan seems higher in patients with unknown primary.

10092 Background: Oxaliplatin induced peripheral neuropathy (OXA-PNP) is a frequent side effect of oxaliplatin containing chemotherapy protocols. It is commonly assessed clinically via physical examination and patient reported symptoms. Research has been impeded by the lack of objective tests to quantify OXA-PNP. Neurophysiological examination is time-consuming and can only cover a selected part of the examined nerve. The aim of this study was to investigate in-vivo morphological correlates of OXA-PNP by magnetic resonance neurography (MRN). Methods: 20 patients with mild to moderate OXA-PNP and 20 matched controls were prospectively enrolled. All patients underwent a detailed neurophysiology examination prior to neuroimaging. A standardized MRN imaging protocol at 3.0 Tesla with large-coverage included the lumbosacral plexus, as well as both sciatic nerves and their branches using T2-weighted fat-saturated sequences at high resolution. Qualitative evaluation of sciatic, tibial, and peroneal nerves were performed by two readers regarding the presence, degree, and distribution of nerve lesions. Quantitative assessment included volumetry of the dorsal root ganglia (DRG) and sciatic nerve normalized T2 (nT2) signal and caliber. Results: Significant DRG hypertrophy in OXA-PNP patients (207.3±47.7mm3 vs. 153.0±47.1mm3 in controls, p = 0.001) was found as morphological correlate of the sensory neuronopathy. Peripheral nerves only exhibited slight morphological alterations qualitatively. Quantitatively, sciatic nerve caliber was unchanged (26.0±5.1mm2 vs. 27.4±7.4mm2, p = 0.19) while sciatic nerve nT2 signal was slightly and non-significantly elevated in patients (1.32±0.22 vs. 1.22±0.26, p = 0.19). Conclusions: OXA-PNP leads to morphological correlates that can be detected in-vivo by MRN. Significant hypertrophy of the DRG was observed, a phenomenon which has not been described in OXA-PNP previously. DRG volume should be investigated as a biomarker in other sensory peripheral neuropathies and ganglionopathies as well as in studies evaluating neuroprotective strategies for OXA-PNP.

4096 Background: Antiresorptive therapy (ART) with bisphosphonates or denosumab is effective in preventing skeletal-related events (SREs) in patients with bone metastases (BM). In neuroendocrine neoplasms (NEN), BM are a negative prognostic factor, however tend to be asymptomatic and SREs are considered a rare event. The role of ART in preventing SREs in NEN has not been investigated so far. Methods: Retrospective analysis of all patients with bone metastases in the NEN database of the National Center for Tumor Diseases who presented at our center between 12/2012 and 01/2017. Overall survival (OS) from diagnosis of BM as well as time to SRE (TTSRE) were calculated. In patients experiencing an SRE within 1 month after diagnosis (i.e. before efficacy of ART could be assessed), TTSRE was defined as the time to a subsequent SRE. Results: In a total of 513 patients in the database, 108 patients with BM could be identified. Median OS was not reached in a median follow-up of 15.2 months. ART was applied to 42.6 % of patients. OS with or without ART did not differ significantly (p = 0.2538). 28.7 % of patients experienced at least 1 SRE, 20.4 % after more than 1 month. Median TTSRE was 63.8 months with ART and 127.0 months without ART (p = 0.1751). TTSRE was shortened in grade 3 vs. grade 1+2 NEN (172 months vs. not reached, HR 4.058, p = 0.0032), as well as in lytic vs. non-lytic metastases (24.5 vs. not reached, HR 7.319, p < 0.0001), however not significantly different in oligometastatic vs. disseminated bone disease (not reached vs. 63,8 months, HR 1.415, p = 0.4287). Application of ART did not significantly change TTSRE in either of these subgroups. Significant toxicity attributable to ART was observed in 15.2 % of ART patients. Conclusions: SREs in NEN patients with BM were not uncommon, especially in patients with grade 3 NEN and osteolytic metastases. Application of ART did not significantly alter median OS or TTSRE, no subgroup with a benefit of ART could be identified. The use of ART in NEN should be questioned and evaluated prospectively.

Trastuzumab-based therapy has significantly changed the management of Her-2 positive metastatic esophagogastric cancer. However, only limited experience exists for the management in patients who are not suitable for cisplatin-based therapy.Patients treated with trastuzumab in combination with different chemotherapeutic regimens were analyzed. Response rates, progression-free survival, overall survival, patterns of cardiac toxicity and patterns of maintenance strategies were recorded.The response rates, progression-free survival and overall survival in patients with metastatic esophagogastric cancer treated with trastuzumab and different chemotherapeutic regimens compared well with the data published in the TOGA trial. No unexpected toxicity occurred. Different strategies were used for therapy de-escalation.Trastuzumab-based therapy is effective in combination with several chemotherapeutic regimens with a safe toxicity pattern. The optimal maintenance strategy remains to be defined.

Several strains of the Newcastle disease virus (NDV) have raised considerable interest in recent years for clinical application because of their oncolytic properties. In this study we characterized virological, immunological and anti-tumor properties of some NDV strains. The oncolytic strain MTH-68/H was the most potent interferon-alpha inducer and, after UV light inactivation, it was the only tested NDV strain which induced in human PBMC anti-tumor activity in vitro. Upon systemic application to mice bearing a virus susceptible intradermal tumor, no significant anti-tumor effects were observed with the two oncolytic strains Italian and MTH-68/H while the treatment had significant side effects as seen by loss of body weight. In contrast, when using a locoregional application model for treatment of liver metastases of luciferase transfected CT26 colon carcinoma cells, MTH-68/H showed a significant delay in tumor growth, as well as prolonged survival but no effects on body weight. Surprisingly, this CT26 murine tumor cell transfectant was resistant in vitro to virus infection and oncolysis. These results suggest: i) that locoregional application of oncolytic NDV is more effective than systemic i.v. application; and ii) that oncolytic NDV can mediate effects even against a virus-resistant tumor line. The involvement of host anti-tumor immune responses as an important mechanism in therapies based on oncolytic NDV will be discussed.

e15187 Background: Mixed adenoneuroendocrine carcinomas (MANEC) are considered a rare disease entity. Commonly they are treated in analogy to adenocarcinomas (AC) or neuroendocrine carcinomas (NEC)...

e15194 Background: Therapeutic options for metastatic poorly differentiated extrapulmonary neuroendocrine carcinoma (NEC) after prior platinum-based chemotherapy are limited. Topotecan is an approv...