Successful implementation of online educational lectures of the German Society for Radiation Oncology (DEGRO).

PURPOSE: Modern digital teaching formats have become increasingly important in recent years, in part due to the COVID-19 pandemic. In January 2021, an online-based webinar series was established by the German Society for Radiation Oncology (DEGRO) and the young DEGRO (yDEGRO) working group. In the monthly 120-minute courses, selected lecturers teach curricular content as preparation for the board certification exam for radiation oncology. METHODS: The evaluation of the 24 courses between 01.2021 and 12.2022 was performed using a standardized questionnaire with 21 items (recording epidemiological characteristics of the participants, didactic quality, content quality). A Likert scale (1-4) was used in combination with binary and open-ended questions. RESULTS: A combined total of 4200 individuals (1952 in 2021 and 2248 in 2022) registered for the courses, and out of those, 934 participants (455 in 2021 and 479 in 2022) later provided evaluations for the respective courses (36% residents, 35% specialists, 21% medical technicians for radiology [MTR], 8% medical physics experts [MPE]). After 2 years, 74% of the DEGRO Academy curriculum topics were covered by the monthly webinars. The overall rating by participants was positive (mean 2021: 1.33 and 2022: 1.25) and exceeded the curriculum offered at each site for 70% of participants. Case-based learning was identified as a particularly well-rated method. CONCLUSION: The DEGRO webinar expands the digital teaching opportunities in radiation oncology. The consistently high number of participants confirms the need for high-quality teaching and underlines the advantages of e­learning methods. Optimization opportunities were identified through reevaluation of feedback from course participants. In its design as a teaching format for a multiprofessional audience, the webinar series could be used as a practice model of online teaching for other disciplines.

Crosstalk between immune checkpoint and DNA damage response inhibitors for radiosensitization of tumors.

PURPOSE: This review article is intended to provide a perspective overview of potential strategies to overcome radiation resistance of tumors through the combined use of immune checkpoint and DNA repair inhibitors. METHODS: A literature search was conducted in PubMed using the terms ("DNA repair* and DNA damage response* and intracellular immune response* and immune checkpoint inhibition* and radio*") until January 31, 2023. Articles were manually selected based on their relevance to the topics analyzed. RESULTS: Modern radiotherapy offers a wide range of options for tumor treatment. Radiation-resistant subpopulations of the tumor pose a particular challenge for complete cure. This is due to the enhanced activation of molecular defense mechanisms that prevent cell death because of DNA damage. Novel approaches to enhance tumor cure are provided by immune checkpoint inhibitors, but their effectiveness, especially in tumors without increased mutational burden, also remains limited. Combining inhibitors of both immune checkpoints and DNA damage response with radiation may be an attractive option to augment existing therapies and is the subject of the data summarized here. CONCLUSION: The combination of tested inhibitors of DNA damage and immune responses in preclinical models opens additional attractive options for the radiosensitization of tumors and represents a promising application for future therapeutic approaches.

Irradiation dose to the swallowing apparatus impacts nutritional status in head and neck cancer patients-results from the prospective randomized HEADNUT trial.

PURPOSE: To investigate the influence of radiation dose to the swallowing muscles on the nutritional status in patients with head and neck cancer undergoing primary or adjuvant (chemo)radiotherapy (C)RT. METHODS: Between 2018 and 2020, 61 patients were prospectively randomized into the so-called HEADNUT trial (head and neck cancer patients undergoing nutritional intervention). Follow-up was continued until 2022. Contouring of the swallowing apparatus included the superior (scm), middle (mcm), and inferior constrictor muscle (icm), the cricopharyngeal muscle (cphm), and the esophageal inlet. Nutritional status was assessed by bioelectrical impedance analysis (BIA) at the beginning and the end of radiotherapy. The posttherapeutic nutritional status was evaluated by the BIA-derived fat-free mass index (FFMI; kg/m2). Malnutrition was assumed at FFMI values of < 15 (women) and < 17 (men) kg/m2. To find differences between dosimetric parameters in well- and malnourished patients, Mann-Whitney U test was used. To model the association between malnutrition and its potentially influencing variables, several logistic regression models were built. RESULTS: The following parameters differed between well- and malnourished patients at the end of therapy: icm Dmean, V40Gy (%), V50Gy (%), and V60Gy (%), and sphm V40Gy (%). After entering these parameters into a multivariable logistic regression model (dosimetric model), icm Dmean (b = -0.12; Exp(b) = 0.88; 95% CI: 0.78-1.0; p = 0.06) and icm V40Gy (%; b = 0.06; Exp(b) = 1.07; 95% CI: 1-1.13; p = 0.04) proved to be independent dosimetric predictors of malnutrition. We only determined the cut-off value for predicting malnutrition for icm V40Gy (%) since it was the only parameter which met p < 0.05. The optimal cut-off value for the predictor V40Gy (%) based on the Youden Index was 85.6%. Another logistic regression model (dosimetric-clinical model) consisted of icm V40 (%) and the clinical parameters tumor localization, malnutrition before RT, gender, and combined chemotherapy. It was confirmed that both icm V40% (b = -1.9; Exp(b) = -2.7; 95% CI: 0.01-0.8; p = 0.03) and malnutrition at baseline (b = -1.9; Exp(b) = 4.4; 95% CI: 8.4-816.6; p = 0.0002) were independent predictors of subsequent malnutrition the end of RT. CONCLUSION: Establishment of a normal nutritional status before the start of RT and adherence to dose constraints for the swallowing apparatus may prevent malnutrition in head and neck cancer patients at the end of therapy. Specifically, we suggest an icm V40Gy (%) of more than 86% to be predictive for nutritional complications.

Risk management patterns in radiation oncology-results of a national survey within the framework of the Patient Safety in German Radiation Oncology (PaSaGeRO) project.

PURPOSE: Risk management (RM) is a key component of patient safety in radiation oncology (RO). We investigated current approaches on RM in German RO within the framework of the Patient Safety in German Radiation Oncology (PaSaGeRO) project. Aim was not only to evaluate a status quo of RM purposes but furthermore to discover challenges for sustainable RM that should be addressed in future research and recommendations. METHODS: An online survey was conducted from June to August 2021, consisting of 18 items on prospective and reactive RM, protagonists of RM, and self-assessment concerning RM. The survey was designed using LimeSurvey and invitations were sent by e­mail. Answers were requested once per institution. RESULTS: In all, 48 completed questionnaires from university hospitals, general and non-academic hospitals, and private practices were received and considered for evaluation. Prospective and reactive RM was commonly conducted within interprofessional teams; 88% of all institutions performed prospective risk analyses. Most institutions (71%) reported incidents or near-events using multiple reporting systems. Results were presented to the team in 71% for prospective analyses and 85% for analyses of incidents. Risk conferences take place in 46% of institutions. 42% nominated a manager/committee for RM. Knowledge concerning RM was mostly rated "satisfying" (44%). However, 65% of all institutions require more information about RM by professional societies. CONCLUSION: Our results revealed heterogeneous patterns of RM in RO departments, although most departments adhered to common recommendations. Identified mismatches between recommendations and implementation of RM provide baseline data for future research and support definition of teaching content.

Teaching in radiation oncology: now and 2025-results of a focus group with medical students.

PURPOSE: In Germany, the new Licensing Regulations for Physicians 2025 (Ärztliche Approbationsordnung, ÄApprO) define a binding legal framework on the basis of which medical faculties modernize their curricula. Since 2015, the National Competence Based Learning Objectives Catalogue for Medicine 2.0 (Nationaler Kompetenzbasierter Lernzielkatalog 2.0., NKLM) formulates competencies and learning objectives to be achieved in the course of studies as curriculum orientation for the medical faculties. In addition, about 80% of the areas of a new core curriculum are to be made compulsory. A needs analysis in the target group of students has not yet taken place for the subject of radiation therapy (RT) or radiation oncology (RO). This study therefore surveys the experiences and requirements of students regarding medical education in RT. METHODS: Qualitative single-center study using a semistructured in-depth focus group with 11 medical students (20-26 years; 6 female, 5 male) was conducted. Brainstorming sessions were conducted in small groups and individually; oral contributions were recorded, transcribed, and analyzed using qualitative content analysis according to Mayring. Results were compared with the content of the future curriculum and reviewed for congruence with current expert recommendations of the German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie, DEGRO). RESULTS: The plans to develop a longitudinal and practice-oriented curriculum was positively received by students. Specifically, students wanted to introduce the basics of RT as an early link to practice in preclinical teaching units. The necessary acquisition of communicative skills should also be taught by lecturers in RO. Methodologically, regular digital survey tools for self-monitoring, discussion rooms, and problem-based learning were named. In the perception of students, the subject appears underrepresented in relation to its relevance in the multimodal therapy of oncological diseases. CONCLUSION: Results of the needs analysis for the subject of RT are consistent with ÄApprO, NKLM, and DEGRO. Moreover, they complement them and should be considered in the curriculum development of Masterplan Medical Education 2020 (Masterplan Medizinstudium 2020). The results contribute to high-quality and target-group-oriented medical training in the subject of RT, increased visibility, and thus early bonding of future physicians to RO in Germany.

Impact of dosimetric factors on long-term percutaneous enteral gastrostomy (PEG) tube dependence in head and neck cancer patients after (chemo)radiotherapy-results from a prospective randomized trial.

PURPOSE/OBJECTIVE: To analyze dose-volume histogram (DVH)-derived data on the exposure of organs at risk with impact on long-term percutaneous enteral gastrostomy (PEG) tube dependence in head and neck cancer patients at 6 and 12 months after definitive or adjuvant (chemo)radiotherapy. MATERIALS AND METHODS: Sixty-one patients were prospectively treated with (chemo)radiotherapy. Prophylactic or reactive gastrostomy tube placement was performed in 41 (67.2%) patients. Dose-volume histogram parameters were obtained for the swallowing apparatus. RESULTS: Median follow-up time was 25 (2-34) months. Overall survival was shorter in patients with inlying PEG tubes at 6 and 12 months (log rank p = 0.038 and p = 0.017) after therapy completion. The estimated median time of tube dependency was 6 (95% confidence interval: 2-14) months. After 6 months, 46.5% of patients were tube dependent. After 12 months, this estimated proportion fell to 31.5%. For both time points, the volume to the larynx (in %) receiving at least 50 Gy (larynx V50Gy) exceeding 53% was predictive for long-term tube feeding (6 months: p = 0.041 and 12 months: p = 0.042) being an independent predictor during multivariable analysis. There was no clinical feature influencing tube dependence after 12 months. CONCLUSION: Long-term gastrostomy dependence was found to be strongly associated with an exposure of laryngeal structures (specifically, V50Gy ≥ 53%) during radiotherapy. Consequently, the avoidance of supraglottic as well as glottic structures is warranted.

The impact of nutritional counseling on thyroid disorders in head and neck cancer patients after (chemo)radiotherapy: results from a prospective interventional trial.

OBJECTIVE: To analyze the impact of nutritional counseling on the development of hypothyroidism after (chemo)radiotherapy in head and neck cancer patients to propose a new normal tissue complication probability (NTCP) model. MATERIALS AND METHODS: At baseline, at the end of (chemo)radiotherapy, and during follow-up, thyroid-stimulating hormone (TSH) with free thyroxin (fT3 and fT4), nutritional status, and nutrient intake were prospectively analyzed in 46 out of 220 screened patients. Patients received (chemo)radiotherapy within an intervention (individual nutritional counseling every 2 weeks during therapy) and a control group (no nutritional counseling). RESULTS: Overall median follow-up was 16.5 [IQR: 12; 22] months. Fourteen patients (30.4%) presented with hypothyroidism after 13.5 [8.8; 17] months. During (chemo)radiotherapy, nutritional status worsened in the entire cohort: body mass index (p < 0.001) and fat-free mass index (p < 0.001) decreased, calorie deficit (p = 0.02) increased, and the baseline protein intake dropped (p = 0.028). The baseline selenium intake (p = 0.002) increased until the end of therapy. Application of the NTCP models by Rønjom, Cella, and Boomsma et al. resulted in good performance of all three models, with an AUC ranging from 0.76 to 0.78. Our newly developed NTCP model was based on baseline TSH and baseline ferritin. Model performance was good, receiving an AUC of 0.76 (95% CI: 0.61-0.87), with a sensitivity of 57.1% and specificity of 96.9% calculated for a Youden index of 0.73 (p = 0.004; area = 0.5). CONCLUSION: Baseline TSH and ferritin act as independent predictors for radiotherapy-associated hypothyroidism. The exclusion of such laboratory chemistry parameters in future NTCP models may result in poor model performance.

DEGRO practical guideline for central nervous system radiation necrosis part 2: treatment.

PURPOSE: The Working Group for Neurooncology of the German Society for Radiation Oncology (DEGRO; AG NRO) in cooperation with members of the Neurooncological Working Group of the German Cancer Society (DKG-NOA) aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS). METHODS: Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN, including bevacizumab, in clinical routine. CONCLUSION: Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neurooncologist. If the diagnosis of blood-brain barrier disruptions (BBD) or RN is likely, treatment should be initiated depending on the symptoms, location, and dynamic of the lesion. Multiple treatment options are available (such as observation, surgery, steroids, and bevacizumab) and the optimal approach should be discussed in an interdisciplinary setting. In this practice guideline, we offer detailed treatment strategies for various scenarios.

DEGRO practical guideline for central nervous system radiation necrosis part 1: classification and a multistep approach for diagnosis.

PURPOSE: The Working Group for Neuro-Oncology of the German Society for Radiation Oncology in cooperation with members of the Neuro-Oncology Working Group of the German Cancer Society aimed to define a practical guideline for the diagnosis and treatment of radiation-induced necrosis (RN) of the central nervous system (CNS). METHODS: Panel members of the DEGRO working group invited experts, participated in a series of conferences, supplemented their clinical experience, performed a literature review, and formulated recommendations for medical treatment of RN including bevacizumab in clinical routine. CONCLUSION: Diagnosis and treatment of RN requires multidisciplinary structures of care and defined processes. Diagnosis has to be made on an interdisciplinary level with the joint knowledge of a neuroradiologist, radiation oncologist, neurosurgeon, neuropathologist, and neuro-oncologist. A multistep approach as an opportunity to review as many characteristics as possible to improve diagnostic confidence is recommended. Additional information about radiotherapy (RT) techniques is crucial for the diagnosis of RN. Misdiagnosis of untreated and progressive RN can lead to severe neurological deficits. In this practice guideline, we propose a detailed nomenclature of treatment-related changes and a multistep approach for their diagnosis.

Adjuvant radiotherapy and local recurrence in vulvar cancer - a subset analysis of the AGO-CaRE-1 study.

BACKGROUND: The impact of adjuvant radiotherapy (RT) to the vulva with regard to prognosis and local recurrence in patients with vulvar squamous cell cancer (VSCC) is poorly described. PATIENTS AND METHODS: In the AGO-CaRE-1 study 1618 patients with primary VSCC FIGO stage ≥ IB, treated between 1998-2008, were documented. In this retrospective subanalysis, 360 patients were included based on the following criteria: nodal involvement (pN+), known RT treatment and known radiation fields. RESULTS: The majority had pT1b/pT2 tumors (n=299; 83.1%). In 76.7%, R0 resection was achieved. 57/360 (15.8%) N+ patients were treated with adjuvant RT to the groins/pelvis and 146/360 (40.5%) received adjuvant RT to the vulva and groins/pelvis. 157/360 (43.6%) patients did not receive any adjuvant RT. HPV status was available in 162/360 patients (45.0%), 75/162 tumors were HPV+(46.3%), 87/162 (53.7%) HPV-. During a median follow-up of 17.2 months, recurrence at the vulva only occurred in 25.5% of patients without adjuvant RT, in 22.8% of patients with adjuvant RT to groins/pelvis and in 15.8% of patients with adjuvant RT to the vulva and groins/pelvis respectively. The risk reducing effect of local RT was independent of the resection margin status. 50% disease free survival time (50% DFST) indicated a stronger impact of adjuvant RT to the vulva in HPV+ compared to HPV- patients (50% DFST 20.7 months vs. 17.8 months). CONCLUSION: Adjuvant RT to the vulva was associated with a lower risk for local recurrence in N+ VSCC independent of the resection margin status. This observation was more pronounced in patients with HPV+ tumors in comparison to HPV- tumors.

Nutritional Status Impacts Quality of Life in Head and Neck Cancer Patients Undergoing (Chemo)Radiotherapy: Results from the Prospective HEADNUT Trial.

Malnutrition negatively impacts quality of life (QoL) in patients with head and neck cancer (HNC). This is the first prospective study to assess the impact of malnutrition (defined by the bioelectrical impedance analysis (BIA)-derived fat-free mass index) on QoL in patients with HNC undergoing (chemo)radiotherapy. Between October 2018 and October 2020, 58 HNC patients prospectively completed the QoL-questionnaires EORTC-QLQ-C30 and EORTC-QLQ-H&N35 at the beginning (tb) and at the end of (chemo)radiotherapy (te) as well as during follow-up (tf). At these time points, nutritional risk assessment (MUST, NRS-2002, Nutriscore), BIA measurement and laboratory testing was performed by a permanent study team. Differences between malnourished (n = 14) and well-nourished patients (n = 44) were observed in UICC classification (P < 0.001) and HPV status (P = 0.03). Well-nourished patients showed higher baseline hemoglobin (P = 0.025) and albumin (P = 0.005), but lower c-reactive protein levels (P < 0.001). At tb, mostly malnourished patients presented with worse QoL. Multivariable analysis showed that MUST, NRS-2002, HPV status, and UICC classification were related to QoL. Nutritional status has a crucial impact on QoL. The nutritional screening protocols MUST and NRS-2002 are suitable for identifying patients at risk and predicting QoL in patients with HNC undergoing (chemo)radiotherapy.

Myocardial injury detected by T1 and T2 mapping on CMR predicts subsequent cancer therapy-related cardiac dysfunction in patients with breast cancer treated by epirubicin-based chemotherapy or left-sided RT.

OBJECTIVES: Cancer therapy-related cardiac dysfunction (CTRCD) is a relevant clinical problem and needs early prediction. This study aimed to analyze myocardial injury using serial laboratory and cardiac magnetic resonance imaging (CMR) parameters after epirubicin-based chemotherapy compared with left-sided radiotherapy and to study their value for early prediction of CTRCD. METHODS: Sixty-six consecutive women (53 ± 13 years) including n = 39 with epirubicin-based chemotherapy and n = 27 with left-sided radiotherapy were prospectively studied by 3 T CMR including left ventricular (LV) mass and volumes for ejection fraction (LVEF), as well as feature-tracking with global longitudinal strain (GLS) and T1/T2 mapping. CMR was performed at baseline, at therapy completion (follow-up 1, FU1), and after 13 ± 2 months (FU2). CTRCD was defined as LVEF decline of at least 10% to < 55% or a > 15% GLS change at FU2. RESULTS: T1 and T2 increased at FU1 after epirubicin-based chemotherapy, but not after left-sided radiotherapy. CTRCD occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy. T1 at FU1 was the best single parameter to predict CTRCD with an area under the curve (AUC) of 0.712 (CI 0.587-0.816, p = 0.005) with excellent sensitivity (100%, 66-100%), but low specificity (44%, 31-58%). Combined use of increased T1 and LVEF ≤ 60% at FU1 improved AUC to 0.810 (0.695-0.896) resulting in good sensitivity (78%, 44-95%) and specificity (84%, 72-92%). CONCLUSION: Only epirubicin-based chemotherapy, but not left-sided radiotherapy, resulted in increased T1/T2 myocardial relaxation times as a marker of myocardial injury. Combined use of CMR parameters may allow an early prediction of subsequent CTCRD. KEY POINTS: • Myocardial T1 and T2 relaxation times increased at FU1 after epirubicin-based chemotherapy, but not after left-sided radiotherapy. • Cancer therapy-related cardiac dysfunction (CTRCD) occurred in 20% of patients after epirubicin-based chemotherapy and in 4% after left-sided radiotherapy. • Combined use of increased T1 and reduced LVEF had an AUC of 0.810 (0.695-0.896) to predict CTRCD with good sensitivity (78%, 44-95%) and specificity (84%, 72-92%).

Partial Reduction in BRCA1 Gene Dose Modulates DNA Replication Stress Level and Thereby Contributes to Sensitivity or Resistance.

BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1. How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.

Analyzing tyrosine kinase activity in head and neck cancer by functional kinomics: Identification of hyperactivated Src family kinases as prognostic markers and potential targets.

Signal transduction via protein kinases is of central importance in cancer biology and treatment. However, the clinical success of kinase inhibitors is often hampered by a lack of robust predictive biomarkers, which is also caused by the discrepancy between kinase expression and activity. Therefore, there is a need for functional tests to identify aberrantly activated kinases in individual patients. Here we present a systematic analysis of the tyrosine kinases in head and neck cancer using such a test-functional kinome profiling. We detected increased tyrosine kinase activity in tumors compared with their corresponding normal tissue. Moreover, we identified members of the family of Src kinases (Src family kinases [SFK]) to be aberrantly activated in the majority of the tumors, which was confirmed by additional methods. We could also show that SFK hyperphosphorylation is associated with poor prognosis, while inhibition of SFK impaired cell proliferation, especially in cells with hyperactive SFK. In summary, functional kinome profiling identified SFK to be frequently hyperactivated in head and neck squamous cell carcinoma. SFK may therefore be potential therapeutic targets. These results furthermore demonstrate how functional tests help to increase our understanding of cancer biology and support the expansion of precision oncology.

Parotid sparing and quality of life in long-term survivors of locally advanced head and neck cancer after intensity-modulated radiation therapy.

PURPOSE: Intensity-modulated radiation therapy (IMRT) enables radiation oncologists to optimally spare organs at risk while achieving homogeneous dose distribution in the target volume. Despite great advances in technology, xerostomia is one of the most detrimental long-term side effects after multimodal therapy in patients with locally advanced head and neck cancer (HNC). This prospective observational study examines the effect of parotid sparing on quality of life in long-term survivors. PATIENTS AND METHODS: A total of 138 patients were grouped into unilateral (n = 75) and bilateral (n = 63) parotid sparing IMRT and questioned at 3, 24, and 60-month follow-up using the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-H&N35 questionnaires. Treatment-related toxicity was scored according to the RTOG/EORTC toxicity criteria. Patients' QoL 24 and 60 months after IMRT was analyzed by ANCOVA using baseline QoL (3 months after IMRT) as a covariate. RESULTS: Patients with bilateral and unilateral parotid-sparing IMRT surviving 60 months experience similar acute and late side effects and similar changes in QoL. Three months after IMRT, physical and emotional function as well as fatigue, nausea and vomiting, pain, dyspnea, and financial problems are below (function scales) or above (symptom scales) the threshold of clinical importance. In both groups, symptom burden (EORTC H&N35) is high independent of parotid sparing 3 months after IMRT and decreases over time in a similar pattern. Pain and financial function remain burdensome throughout. CONCLUSION: Long-term HNC survivors show a similar treatment-related toxicity profile independent of unilateral vs. bilateral parotid-sparing IMRT. Sparing one or both parotids had no effect on global QoL nor on the magnitude of changes in function and symptom scales over the observation period of 60 months. The financial impact of the disease and its detrimental effect on long-term QoL pose an additional risk to unmet needs in this special patient population. These results suggest that long-term survivors need and most likely will benefit from early medical intervention and support within survivorship programs.

Radiochemotherapy with or without cetuximab for unresectable esophageal cancer: final results of a randomized phase 2 trial (LEOPARD-2).

PURPOSE: To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer. METHODS: This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2­year overall survival (OS). Arm A was considered insufficiently active if 2­year OS was ≤40% (null hypothesis = H0), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable. RESULTS: Two-year OS was 71% in arm A (95% CI: 55-87%) vs. 53% in arm B (95% CI: 36-71%); H0 was rejected. Median OS was 49.1 vs. 24.1 months (p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30-1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25-1.04) for progression, 0.43 (0.13-1.40) for locoregional failure, and 0.43 (0.17-1.05) for distant metastasis. Overall response was 81% vs. 69% (p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 (p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044). CONCLUSION: Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.

Implementation analysis of patient reported outcomes (PROs) in oncological routine care: an observational study protocol.

BACKGROUND: The successful implementation of patient-reported outcomes (PROs) in clinical routine faces many challenges, first and foremost the lack of consideration thereof in the patient care process. The aim of this study will be to first identify relevant barriers and facilitators and then design suitable implementation strategies which will be evaluated to improve the effectiveness of a PRO measure assessment in inpatient and outpatient cancer routine care. METHODS: During the preparation phase, interviews with oncological patients (N = 28) and medical staff (N = 4) as well as focus groups with medical staff (N = 18) across five different departments caring for cancer patients were conducted. On the basis of these, qualitative content analysis revealed relevant barriers and facilitators for implementation of PROs in cancer care. Subsequently, implementation strategies and a model of implementation were developed. In the study phase, implementation strategies will be evaluated based on nine different implementation outcomes in five different oncological clinics. Evaluation of the implementation process will take place during three months in each clinic and data will be conducted pre, while and post implementation of the PRO measure. Therefore a sample size of 60 participants of whom 30 staff members and 30 participants will be questioned using existing and newly developed implementation outcome evaluation instruments. DISCUSSION: Key to improving the effectiveness of PRO assessment in the time-critical clinical environment is the utilization of easy-to-use, electronic PRO questionnaires directly linked to patients' records thereby improving consideration of PROs in patient care. In order to validate the effectiveness of this implementation process further, an evaluation parallel to implementation following an observational study design with a mixed-methods approach will be conducted. This study could contribute to the development of adequate evaluation processes of implementation of PROs to foster sustainable integration of PRO measures into routine cancer care. TRIAL REGISTRATION: This study was registered at Open Science Framework (https://osf.io/y7xce/).

Cerebral metastasis in recurrent squamous cell carcinoma of the vulva: case report and review of the literature.

BACKGROUND: Distant metastases from squamous cell cancer of the vulva (VSCC) are encountered rarely and are associated with a poor prognosis. Cerebral metastases have only been described anecdotally. CASE HISTORY: A 51-year old woman was diagnosed with hepatic metastases due to VSCC. Initial therapy comprised wide local excision of the primary tumor with inguino-femoral lymphadenectomy (LAE) followed by stereotactic radiation of the singular hepatic metastasis while adjuvant chemoradiation of the vulva and lymphatics was declined. 3 years later, she subsequently developed lung and cerebral metastases. CONCLUSION: The course of metastatic disease in VSCC is poorly understood. Further knowledge of the metastatic patterns in vulvar cancer is required for guidance of future therapeutic interventions.

Clonality of circulating tumor cells in breast cancer brain metastasis patients.

BACKGROUND: The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. METHODS: Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). RESULTS: CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status (p = 0.029) of the primary tumor as well as with the prevalence of bone metastases (p = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time (p < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation. CONCLUSION: The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment.

A functional ex vivo assay to detect PARP1-EJ repair and radiosensitization by PARP-inhibitor in prostate cancer.

Here, we present a functional assay to detect the repair switch to the alternative PARP1-dependent end joining (PARP1-EJ) pathway and the associated susceptibility to PARPi-mediated radiosensitization in freshly collected tumor samples from prostate cancer (PCa) patients, thereby facilitating the selection of patients who should benefit from combined PARPi plus radiotherapy (RT) treatment. Our optimized ex-vivo approach sustains tumor slices for up to 15 days under culture conditions that maintain proliferation and oxygenation rates, as measured by EdU incorporation and pimonidazole staining, respectively. We present a robust system to analyze DSB repair using, for the first time in an ex vivo tumor slice setting, two DSB-markers simultaneously i.e. γH2AX and 53BP1. A computer-based processing method (i) controls variations in DNA content and slicing on the number of repair foci and (ii) measures the PARPi-mediated enhancement ratio on DSB foci numbers to ensure inter-patient-comparability. We validated this approach using a PC3 xenograft model with its previously described repair switch to PARP1-EJ. More importantly, we show that approximately 30% of the analyzed tumor tissue samples collected from PCa patients display a switch to PARP1-EJ, as indicated by the enhanced number of residual γH2AX/53BP1 foci exclusively after PARPi+RT. Furthermore, normal prostatic tissues show no repair switch to PARP1-EJ, indicating that this repair switch and its associated radiosensitizing effect is tumor-specific. Collectively, we present here a predictive assay for the switch to PARP1-EJ that enables individualization of anti-cancer treatment using a combination of RT and radiosensitizing anticancer agents such as PARPi in PCa.