Patterns of Temporal Lobe Reaction and Radiation Necrosis after Particle Radiotherapy in Patients with Skull Base Chordoma and Chondrosarcoma-A Single-Center Experience.

BACKGROUND: The current study aims to evaluate the occurrence of temporal lobe reactions and identify possible risk factors for patients who underwent particle therapy of the skull base. METHODS: 244 patients treated for skull base chordoma (n = 144) or chondrosarcoma (n = 100) at the Heidelberg Ion Beam Therapy Center (HIT) using a raster scan technique, were analyzed. Follow-up MRI-scans were matched with the initial planning images. Radiogenic reactions were contoured and analyzed based on volume and dose of treatment. RESULTS: 51 patients with chordoma (35.4%) and 30 patients (30%) with chondrosarcoma experienced at least one temporal lobe reaction within the follow-up period (median 49 months for chondrosarcoma, 62 months for chordoma). Age, irradiated volume, and dose values were significant risk factors for the development of temporal lobe reactions with the highest significance for the value of DMax-7 being defined as the dose maximum in the temporal lobe minus the 7cc with the highest dose (p = 0.000000000019; OR 1.087). CONCLUSION: Temporal lobe reactions are a common side effect after particle therapy of the skull base. We were able to develop a multivariate model, which predicted radiation reactions with a specificity of 99% and a sensitivity of 52.2%.

Oncologic treatment support via a dedicated mobile app: a prospective feasibility evaluation (OPTIMISE-1).

BACKGROUND: Mobile health (mhealth) is gaining interest, with mobile devices and apps being ever more available among medical facilities and patients. However, in the field of radiation oncology, the medical benefits of mhealth apps are still underexplored. As an additional approach to patient care during radiotherapy, we designed a mobile treatment surveillance app based on patient-reported outcomes. OBJECTIVE: We aimed to examine the feasibility of app-based treatment surveillance in patients undergoing radiotherapy (RT). Alongside technical practicability and acceptance, we assessed patient satisfaction and quality of life during treatment. METHODS: This prospective single-center study was performed at Heidelberg University Hospital between August 2018 and January 2020. During RT we measured patients' quality of life, symptoms, and treatment satisfaction. Respective questionnaires (EORTC QLQ-C30 with diagnosis-specific modules, RAND PSQ-18) were presented to patients via a mobile app running on a designated tablet device. The primary endpoint was determined by the fraction of patients who completed at least 80% of the items. Secondary endpoints were disease-related quality of life and patient satisfaction. RESULTS: A total of 49 cancer patients (14 breast, 13 pelvic, 12 lung, 10 prostate) were eligible for analysis. 79.6% (95% confidence interval: 66.4-88.5%; n = 39) of all patients completed at least 80% of the items received by the mobile app. A mean of 227.5 ± 48.25 questions were answered per patient. Breast cancer patients showed the highest rate of answered questions, with 92.9% (n = 13) completing at least 80% of the items. CONCLUSION: Patients showed high acceptance, with 79.6% (n = 39) completing at least 80% of the given items. The use of a mobile app for reporting symptoms and quality of life during RT is feasible and well accepted by patients. It may allow for resource-efficient, detailed feedback to the medical staff and assist in the assessment of side effects over time.

Software-Tool Support for Collaborative, Virtual, Multi-Site Molecular Tumor Boards.

The availability of high-throughput molecular diagnostics builds the foundation for Molecular Tumor Boards (MTBs). Although more fine-grained data is expected to support decision making of oncologists, assessment of data is complex and time-consuming slowing down the implementation of MTBs, e.g., due to retrieval of the latest medical publications, assessment of clinical evidence, or linkage to the latest clinical guidelines. We share our findings from analysis of existing tumor board processes and defininion of clinical processes for the adoption of MTBs. Building on our findings, we have developed a real-world software prototype together with oncologists and medical professionals, which supports the preparation and conduct of MTBs and enables collaboration between medical experts by sharing medical knowledge even across the hospital locations. We worked in interdisciplinary teams of clinicians, oncologists, medical experts, medical informaticians, and software engineers using design thinking methodology. With their input, we identified challenges and limitations of the current MTB approaches, derived clinical process models using Business Process and Modeling Notation (BMPN), and defined personas, functional and non-functional requirements for software tool support. Based on it, we developed software prototypes and evaluated them with clinical experts from major university hospitals across Germany. We extended the Kanban methodology enabling holistic tracking of patient cases from "backlog" to "follow-up" in our app. The feedback from interviewed medical professionals showed that our clinical process models and software prototype provide suitable process support for the preparation and conduction of molecular tumor boards. The combination of oncology knowledge across hospitals and the documentation of treatment decision can be used to form a unique medical knowledge base by oncologists for oncologists. Due to the high heterogeneity of tumor diseases and the spread of the latest medical knowledge, a cooperative decision-making process including insights from similar patient cases was considered as a very valuable feature. The ability to transform prepared case data into a screen presentation was recognized as an essential feature speeding up the preparation process. Oncologists require special software tool support to incorporate and assess molecular data for the decision-making process. In particular, the need for linkage to the latest medical knowledge, clinical evidence, and collaborative tools to discuss individual cases were named to be of importance. With the experiences from the COVID-19 pandemic, the acceptance of online tools and collaborative working is expected to grow. Our virtual multi-site approach proved to allow a collaborative decision-making process for the first time, which we consider to have a positive impact on the overall treatment quality.

Vaginal cancer treated with curative radiotherapy with or without concomitant chemotherapy: oncologic outcomes and prognostic factors.

BACKGROUND: Vaginal cancer is a rare disease for which prospective randomized trials do not exist. We aimed to assess survival outcomes, patterns of recurrence, prognostic factors, and toxicity in the curative treatment using image-guided radiotherapy (RT). METHODS: In this retrospective review, we identified 53 patients who were treated at a single center with external beam radiotherapy and brachytherapy with or without concomitant chemotherapy from 2000 to 2021. RESULTS: With a median follow-up of 64.5 months, the Kaplan-Meier 2-, 5-, and 7-year overall survival (OS) was found to be 74.8%, 62.8%, and 58.9%, respectively. Local and distant control were 67.8%, 65.0%, and 65.0% and 74.4%, 62.6%, and 62.6% at 2, 5, and 7 years, respectively. In univariate Cox proportional hazards ratio analysis, OS was significantly correlated to FIGO stage (hazard ratio [HR] 1.78, p = 0.042), postoperative RT (HR 0.41, p = 0.044), and concomitant chemotherapy (HR 0.31, p = 0.009). Local control rates were superior when an equivalent dose in 2-Gy fractions (EQD2) of ⩾65 Gy was delivered (HR 0.216, p = 0.028) and with the use of concurrent chemotherapy (HR 0.248, p = 0.011). Not surprisingly, local control was inferior for patients with a higher TNM stage (HR 3.303, p = 0.027). Minimal toxicity was observed with no patients having documentation of high-grade toxicity (CTCAE grade 3+). CONCLUSION: In treatment of vaginal cancer, high-dose RT in combination with brachytherapy is well tolerated and results in effective local control rates, which significantly improve with an EQD2(α/ß=10) ⩾65 Gy. Multivariate analyses revealed concomitant chemotherapy was a positive prognostic factor for overall and progression-free survival.

Coronary artery disease, left ventricular function and cardiac biomarkers determine all-cause mortality in cancer patients-a large monocenter cohort study.

Cancer patients are at risk of suffering from cardiovascular diseases (CVD). Nevertheless, the impact of cardiovascular comorbidity on all-cause mortality (ACM) in large clinical cohorts is not well investigated. In this retrospective cohort study, we collected data from 40,329 patients who were subjected to cardiac catherization from 01/2006 to 12/2017 at University Hospital Heidelberg. The study population included 3666 patients with a diagnosis of cancer prior to catherization and 3666 propensity-score matched non-cancer patients according to age, gender, diabetes and hypertension. 5-year ACM in cancer patients was higher with a reduced left ventricular function (LVEF < 50%; 68.0% vs 50.9%) or cardiac biomarker elevation (high-sensitivity cardiac troponin T (hs-cTnT; 64.6% vs 44.6%) and N-terminal brain natriuretic peptide (NT-proBNP; 62.9% vs 41.4%) compared to cancer patients without cardiac risk. Compared to non-cancer patients, NT-proBNP was found to be significantly higher (median NT-proBNP cancer: 881 ng/L, IQR [254; 3983 ng/L] vs non-cancer: 668 ng/L, IQR [179; 2704 ng/L]; p < 0.001, Wilcoxon-rank sum test) and turned out to predict ACM more accurately than hs-cTnT (NT-proBNP: AUC: 0.74; hs-cTnT: AUC: 0.63; p < 0.001, DeLong's test) in cancer patients. Risk factors for atherosclerosis, such as diabetes and age (> 65 years) were significant predictors for increased ACM in cancer patients in a multivariate analysis (OR diabetes: 1.96 (1.39-2.75); p < 0.001; OR age > 65 years: 2.95 (1.68-5.4); p < 0.001, logistic regression). Our data support the notion, that overall outcome in cancer patients who underwent cardiac catherization depends on cardiovascular comorbidities. Therefore, particularly cancer patients may benefit from standardized cardiac care.

Proton and carbon ion beam treatment with active raster scanning method in 147 patients with skull base chordoma at the Heidelberg Ion Beam Therapy Center-a single-center experience.

BACKGROUND: This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results. METHODS: A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors. RESULTS: During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1­year, 3­year, and 5­year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation. CONCLUSION: Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation.

Deep Learning-based Automatic Lung Segmentation on Multiresolution CT Scans from Healthy and Fibrotic Lungs in Mice.

Purpose: To develop a model to accurately segment mouse lungs with varying levels of fibrosis and investigate its applicability to mouse images with different resolutions. Materials and Methods: In this experimental retrospective study, a U-Net was trained to automatically segment lungs on mouse CT images. The model was trained (n = 1200), validated (n = 300), and tested (n = 154) on longitudinally acquired and semiautomatically segmented CT images, which included both healthy and irradiated mice (group A). A second independent group of 237 mice (group B) was used for external testing. The Dice score coefficient (DSC) and Hausdorff distance (HD) were used as metrics to quantify segmentation accuracy. Transfer learning was applied to adapt the model to high-spatial-resolution mouse micro-CT segmentation (n = 20; group C [n = 16 for training and n = 4 for testing]). Results: The trained model yielded a high median DSC in both test datasets: 0.984 (interquartile range [IQR], 0.977-0.988) in group A and 0.966 (IQR, 0.955-0.972) in group B. The median HD in both test datasets was 0.47 mm (IQR, 0-0.51 mm [group A]) and 0.31 mm (IQR, 0.30-0.32 mm [group B]). Spatially resolved quantification of differences toward reference masks revealed two hot spots close to the air-tissue interfaces, which are particularly prone to deviation. Finally, for the higher-resolution mouse CT images, the median DSC was 0.905 (IQR, 0.902-0.929) and the median 95th percentile of the HD was 0.33 mm (IQR, 2.61-2.78 mm). Conclusion: The developed deep learning-based method for mouse lung segmentation performed well independently of disease state (healthy, fibrotic, emphysematous lungs) and CT resolution.Keywords: Deep Learning, Lung Fibrosis, Radiation Therapy, Segmentation, Animal Studies, CT, Thorax, Lung Supplemental material is available for this article. Published under a CC BY 4.0 license.

Frequency of osteoradionecrosis of the lower jaw after radiotherapy of oral cancer patients correlated with dosimetric parameters and other risk factors.

OBJECTIVES: Osteoradionecrosis (ORN) of the lower jaw is a serious late complication after radiotherapy in patients with oral cavity cancer. The aim of this study is to generate more insight into which patient- and treatment-related factors are associated with the development of ORN in oral cavity cancer patients undergoing postoperative radiotherapy. MATERIAL AND METHODS: Retrospective evaluation and comparison of 44 patients with ORN (event group 1) matched according to 45 patients without ORN (control group 2) who received postoperative radiotherapy of oral cavity squamous cell carcinoma at our institution between 2012 and 2020. Dosimetric factors that favor the occurrence of ORN should be detected. The cumulative occurrence rate of ORN was calculated according to the Kaplan-Meier method and analyzed by Cox regression and log-rank test. RESULTS: The median time to develop ORN was 18 months (3-93 months) after radiotherapy. Dental status before radiotherapy (RT) treatment (HR 4.5; 1.8-11.5) and dosimetric parameters including Dmean > 45 Gy (HR 2.4; 1.0-5.7), Dmax > 60 Gy (HR 1.3; 1.1-2.8) and planning target volume (PTV) proportion > 40% intersection with the lower jaw (HR 1.1; 1.0-1.1) were significantly associated with ORN. CONCLUSION: The results of this retrospective study reveal that oral cavity cancer patients who underwent pre-RT dental surgery as well as dosimetric parameters using Dmax > 60 Gy, higher mean doses > 45 Gy and more than 40% PTV intersection with the lower jaw bone are independent risk factors for ORN. These findings can assist in the management of patients undergoing RT for head and neck cancer regarding ORN prevention. CLINICAL RELEVANCE: Poor oral hygiene and desolate dental status as well as high radiation doses to the mandibular bone significantly increase the risk of developing osteoradionecrosis. Before irradiating a patient with oral cavity cancer, an appointment with the dentist should be made and teeth sanitized if necessary. Likewise, maximum radiation doses to the lower jaw should be minimized.

Retrospective analysis of outcome and toxicity after postoperative radiotherapy in patients with squamous cell carcinoma of the lip.

BACKGROUND: Carcinomas of the lips are a relatively common malignancy of the head and neck region, accounting for roughly one quarter of all oral cavity cancers. Compared to other oral cancer sites, this location has a favorable prognosis, with 5-year survival rates between 85% and 95%. This study summarizes our institutional experience in utilizing postoperative radiation for patients with squamous cell carcinoma of the upper and/or lower lip following incomplete surgical resection or positive lymph node involvement with extracapsular extension. METHODS: We retrospectively reviewed the medical records of all patients at the University Hospital of Heidelberg between 2005 and 2018 treated with postoperative radiotherapy of the upper and lower lip. Nineteen patients were identified with a median age at diagnosis of 67 years (range, 41-95 years), with 58% male and 42% female patients. Fourteen patients (73.7%) underwent neck dissection, with 5 (35.7%) found to have extracapsular extension (ECE) and positive resection margin (R1/2), 2 (14.3%) only ECE, and 7 (50.0%) with only R1/2. All patients received a median cumulative dose of 66.0 Gy (range, 60.0-70.0 Gy) in a median of 2.0 Gy per fraction (range, 1.8-2.2 Gy). RESULTS: Median follow-up was 5.2 years. The median progression-free survival (PFS) was 3.9 years (range, 0.2-12.4 years), local disease-free survival (LDFS) was 4 years (range, 1-12 years) and overall survival (OS) was 5.2 years (range, 0.2-12.4 years). The 5-year Kaplan-Meier estimates for OS, PFS, and LDFS were 61.4%, 85.7%, and 100.0%, respectively. At last follow-up, 13 patients (68.4%) were still alive. Although no patient developed locoregional relapse, two patients developed distant relapse at a median of 15 months after radiotherapy. There was a statistically significant improvement in OS in patients treated with higher radiotherapy doses (>60.0 Gy, p = 0.044) compared to lower radiotherapy doses. PFS was significantly improved among patients who had N0 disease, with a negative resection margin, without ECE, and who were treated with intensity-modulated radiotherapy to doses >60.0 Gy. No grade 3/4 toxicity was detected; the most common grade 1/2 toxicities included dermatitis (n = 11, 57.9%), oral mucositis (n = 8, 42.1%), and dysphagia (n = 8, 42.1%). CONCLUSION: Our results demonstrate excellent local control and OS with acceptable toxicity when utilizing postoperative radiotherapy in patients with squamous cell carcinoma of the upper and lower lip, despite unfavorable characteristics (advanced T or N stage and/or ECE).

Definitive radiotherapy for squamous cell carcinoma of the oral cavity: a single-institution experience.

BACKGROUND: Surgery is standard of care for oral cavity cancer (OCC). We provide a single-institution experience using definitive radiotherapy (RT) with or without concurrent systemic therapy for primary unresectable OCC. PATIENTS AND METHODS: We retrospectively examined 49 patients with non-metastatic primary unresectable OCC treated with definitive RT between 2000 and 2019. The majority of patients (63.3%) were treated with definitive chemoradiotherapy while 26.5% were given single-agent cetuximab weekly simultaneous to definitive RT. Five patients were treated with definitive RT alone because of limited disease and no nodal involvement. RESULTS: Median follow-up was 73 months (range, 6-236 months), median progression free survival (PFS) was 42 months (range, 2-157 months), median local disease-free survival (LDFS) was 44 months (range, 2-157 months) and median overall survival (OS) from the time of RT initiation was 52 months (range, 5-236 months). There were 65.3% locoregional failures, 84.4% local and 15.6% distant metastasis. The majority of patients with local failure presented with American Joint Committee on Cancer (AJCC) Stage III-IV disease (59.2%). The 5-year Kaplan-Meier estimates for OS (III-IV vs. I-II) was 22.8% vs. 54.2 % (p = 0.03, HR 2.090, 1.1-4.2). Patients who were treated with systemic therapy had a significant better 5-year overall survival compared to those with RT alone (43.9% vs. 23.1%, p = 0.05, 1.0-4.1). RT with doses less than 70 Gy (p = 0.046, HR 2.1 (1.0-4.5) was associated with worse overall survival. Mucositis was the most common ≥ grade 3 acute toxicity and occurred in 19 patients (39%). Incidences of chronic toxicities were loss of taste, trismus, osteoradionecrosis and xerostomia. CONCLUSIONS: Definitive RT with or without concurrent systemic agents in patients with unresectable OCC resulted in an eloquent rate of locoregional control and good overall survival rates and is currently the best available treatment option in this patient collective.

High-sensitivity cardiac troponin T determines all-cause mortality in cancer patients: a single-centre cohort study.

AIMS: Cardio-oncology is a growing interdisciplinary field which aims to improve cardiological care for cancer patients in order to reduce morbidity and mortality. The impact of cardiac biomarkers, echocardiographic parameters, and cardiological assessment regarding risk stratification is still unclear. We aimed to identify potential parameters that allow an early risk stratification of cancer patients. METHODS AND RESULTS: In this cohort study, we evaluated 930 patients that were admitted to the cardio-oncology outpatient clinic of the University Hospital Heidelberg from January 2016 to January 2019. We performed echocardiography, including Global Longitudinal Strain (GLS) analysis and measured cardiac biomarkers including N-terminal pro brain-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin T levels (hs-cTnT). Most patients were suffering from breast cancer (n = 450, 48.4%), upper gastrointestinal carcinoma (n = 99, 10.6%) or multiple myeloma (n = 51, 5.5%). At the initial visit, we observed 86.7% of patients having a preserved left ventricular ejection fraction (LVEF >50%). At the second follow up, still 78.9% of patients showed a preserved LVEF. Echocardiographic parameters or elevation of NT-proBNP did not significantly correlate with all-cause mortality (ACM) (logistic regression LVEF <50%: P = 0.46, NT-proBNP: P = 0.16) and failed to identify high-risk patients. In contrast, hs-cTnT above the median (≥7 ng/L) was an independent marker to determine ACM (multivariant logistic regression, OR: 2.21, P = 0.0038) among all included patients. In particular, hs-cTnT levels before start of a chemotherapy were predictive for ACM. CONCLUSIONS: Based on our non-selected cohort of cardio-oncological patients, hs-cTnT was able to identify patients with high mortality by using a low cutoff of 7 ng/L. We conclude that measurement of hs-cTnT is an important tool to stratify the risk for mortality of cancer patients before starting chemotherapy.

Knowledge bases and software support for variant interpretation in precision oncology.

Precision oncology is a rapidly evolving interdisciplinary medical specialty. Comprehensive cancer panels are becoming increasingly available at pathology departments worldwide, creating the urgent need for scalable cancer variant annotation and molecularly informed treatment recommendations. A wealth of mainly academia-driven knowledge bases calls for software tools supporting the multi-step diagnostic process. We derive a comprehensive list of knowledge bases relevant for variant interpretation by a review of existing literature followed by a survey among medical experts from university hospitals in Germany. In addition, we review cancer variant interpretation tools, which integrate multiple knowledge bases. We categorize the knowledge bases along the diagnostic process in precision oncology and analyze programmatic access options as well as the integration of knowledge bases into software tools. The most commonly used knowledge bases provide good programmatic access options and have been integrated into a range of software tools. For the wider set of knowledge bases, access options vary across different parts of the diagnostic process. Programmatic access is limited for information regarding clinical classifications of variants and for therapy recommendations. The main issue for databases used for biological classification of pathogenic variants and pathway context information is the lack of standardized interfaces. There is no single cancer variant interpretation tool that integrates all identified knowledge bases. Specialized tools are available and need to be further developed for different steps in the diagnostic process.

Efficacy and Safety of Checkpoint Inhibitor Treatment in Patients with Advanced Renal or Urothelial Cell Carcinoma and Concomitant Chronic Kidney Disease: A Retrospective Cohort Study.

Background: Checkpoint inhibitors are a standard of care in the treatment of advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC). Patients with these tumors often suffer from concomitant chronic kidney disease (CKD). Limited data are available on the efficacy and toxicity of checkpoint inhibitors in patients with CKD. Methods: We retrospectively analyzed 126 patients who received checkpoint inhibitors for RCC (n = 85) or UC (n = 41) and analyzed the frequency of treatment- and immune-related adverse events (AEs). We performed a multivariate analysis to determine progression-free survival (PFS) and overall survival (OS). Results: A total of 38.9% of patients had CKD. Frequencies of general AEs (49.0% in CKD vs. 48.1%, p > 0.99999) and immune-related AEs (28.6 vs. 24.7%, p ≥ 0.9999) did not significantly differ between the groups. There was no difference in PFS for patients with RCC or UC and CKD or without CKD (RCC: 6.81 vs. 7.54 months, HR 1.000 (95%CI 0.548-01.822), p = 0.999; UC:2.33 vs. 3.67 months, HR 01.492 (95%CI 0.686-3.247), p = 0.431). CKD appeared to be a potential effect modifier for OS in both RCC and UC (RCC: NR vs. 23.9 months, HR 0.502 (95%CI 0.219-1.152), p = 0.104; UC:18.84 vs. 15.42 months, HR 0.656 (95%CI 0.296-1.454), p = 0.299). Conclusions: Checkpoint inhibitor treatment in our cohort of patients with CKD was as safe and efficient as in the cohort of patients without CKD.

Metastatic Acinar Cell Carcinoma of the Pancreas: A Retrospective Cohort Study on Systemic Chemotherapy and Review of the Literature.

OBJECTIVES: Acinar cell carcinoma of the pancreas (pACC) forms a rare subgroup of pancreatic tumors. We report on our institutional experience with systemic first- and further-line therapy in patients with metastatic pACC and embed our findings in a review of the literature. METHODS: Patients with stage IV pACC who started systemic treatment between 2008 and 2019 at our institution were identified via our institutional database. Clinical data were extracted from the patients' electronic data records. Survival times were calculated by the Kaplan-Meier method. RESULTS: Six patients received a fluoropyrimidine- and oxaliplatin-containing first-line treatment, and 4 patients were started on gemcitabine-based protocols. Median progression-free survival was 4.8 months [95% confidence interval (CI), 3.3 to not available (n.a.)], and median overall survival was 15.3 months (95% CI, 10.1 to n.a.). Residual survival for second-line treatment was 2.1 months (95% CI, 1.3 to n.a.), although 1 patient experienced almost complete remission under targeted therapy. CONCLUSIONS: The most encouraging and deep responses result from poly-chemotherapy with leucovorin, 5-fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), which seems to be the appropriate choice in fit patients. Gemcitabine monotherapy seems without substantial activity in pACC. Whenever possible, patients with pACC should be screened for targetable mutations.

The role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma.

BACKGROUND: To investigate the role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma; final analysis of a one-armed, single center phase I/II trial. METHODS: Between August 2011 until September 2018, 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) inoperable pelvic (70%) or craniofacial (30%) osteosarcoma were treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) and followed until May 2019. A Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed before CIBRT in search for a prognostic factor. The primary endpoint was toxicity. Secondary endpoints included treatment response, global, local and distant progression free survival (PFS, LPFS and DPFS) and overall (OS), among others. RESULTS: The median age was 20; all patients finished treatment per protocol. LPFS, DPFS, PFS and OS were 73%, 74%, 60% and 75% after one year and 55%, 65% 65.3%, 45% and 68% after two years, respectively. The median clinical target volume (CTV) was 1042 cc and 415 cc for the primary and boost plan, respectively. Craniofacial localization, lower uptake of FDG in PET/CT and boost plan CTV ≤ median were associated with improved overall survival (p = 0.039, p = 0.016 and p = 0.0043, respectively). No acute toxicities > grade III were observed. We observed one case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss. CONCLUSION: CIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma.

Consolidation Immunotherapy After Platinum-Based Chemoradiotherapy in Patients With Unresectable Stage III Non-Small Cell Lung Cancer-Cross-Sectional Study of Eligibility and Administration Rates.

INTRODUCTION: The PACIFC trial demonstrated a significant benefit of durvalumab consolidation immunotherapy (CIT) after definitive platinum-based chemoradiotherapy (P-CRT) for survival in stage III non-small cell lung cancer (NSCLC). It is unknown how many patients are eligible in clinical practice to receive CIT according to PACIFIC criteria compared to real administration rates and what influencing factors are. PATIENTS AND METHODS: We analyzed 442 patients with unresectable stage III NSCLC who received P-CRT between 2009 and 2019 regarding CIT eligibility rates according to PACIFIC criteria and administration rates since drug approval. RESULTS: Sixty-four percent of 437 patients were male, median age was 63 years [interquartile range (IQR): 57-69]. The most common histologic subtypes were adenocarcinoma (42.8%) and squamous cell carcinoma (41.1%), most tumors were in stage IIIB (56.8%). Mean PD-L1 tumor proportion score (TPS) was 29.8% (IQR: 1-60). The median total RT dose was 60 Gy (IQR: 60-66). Platinum component of P-CRT was evenly distributed between cisplatin (51.4%) and carboplatin (48.6%). 50.3% of patients were eligible for CIT according to PACIFIC criteria. Observed contraindications were progressive disease according to RECIST (32.4%), followed by a PD-L1 TPS < 1% (22.3%), pneumonitis CTCAE ≥ 2 (12.6%) and others (4.9%). One year after drug approval, 85.6% of patients who were eligible according to PACIFIC criteria actually received CIT. Time interval between chemotherapy start and radiation therapy start (OR 0.9, 95% CI: [0.9; 1.0] p = 0.009) and probably cisplatin as platinum-component of P-CRT (OR 1.5, 95% CI: [1.0; 2.4] p < 0.061) influence CIT eligibility. Highly positive PD-L1 TPS (≥50%; (OR 2.4, 95% CI: [1.3; 4.5] p = 0.004) was associated to a better chance for CIT eligibility. CONCLUSION: Eighty-five percent of potentially eligible patients received CIT one year after drug approval. Fifty percent of patients did not meet PACIFIC criteria for durvalumab eligibility, this was mainly caused by disease progression during platinum-based CRT, followed by therapy-related pneumonitis and PD-L1 TPS < 1% (in view of the EMA drug approval).

Percutaneous Endoscopic Gastrostomy Tube Placement in Patients with Head and Neck Cancer Treated with Radiotherapy.

BACKGROUND AND AIM: The primary aim of our study was to evaluate percutaneous endoscopic gastrostomy (PEG) tube placement depending on body weight and body mass index in patients undergoing radiotherapy (RT) for head and neck cancer (HNC). A secondary aim was to evaluate the course of weight change following PEG placement. METHODS: We retrospectively reviewed the medical records of 186 patients with HNC undergoing radiotherapy (RT) or chemoradiotherapy (CRT) at our institution between January 2010 and August 2017. Initial weight and nutritional intake were analyzed prior to RT initiation and then followed throughout treatment until completion. Based on these data, the indication of PEG placement was determined. Medical records were also reviewed to analyze PEG-related acute toxicities. RESULTS: A total of 186 patients met inclusion criteria. Patients were most commonly male (n=123, 66.1%) with squamous cell carcinoma (n=164, 88.2%). Patients who had dysphagia prior to treatment initiation as well as patients with a BMI <18.5 kg/m2 needed PEG placement earlier during the treatment course. Low-grade toxicities related to PEG insertion were observed in 10.7% patients, with peristomal pain and redness adjacent to the PEG tube insertion site being most common. High-grade toxicities, such as peritonitis and organ injury, were found in 4.9% of patients. CONCLUSION: Underweight patients and those with preexisting dysphagia should be closely screened during RT for weight loss and decreased oral intake. For weight loss greater than 4.5% during the treatment of HNC, early PEG-tube placement should be considered. Further prospective studies are needed to confirm these findings, and delineate a scoring system for timing of PEG use (prophylactic vs reactive) as well as assess the quality of life in patients with HNC who receive PEG placement.

Dosimetric Impact of Interfractional Variations in Prostate Cancer Radiotherapy-Implications for Imaging Frequency and Treatment Adaptation.

Background and purpose: To analyze deviations of the applied from the planned doses on a voxel-by-voxel basis for definitive prostate cancer radiotherapy depending on anatomic variations and imaging frequency. Materials and methods: Daily in-room CT imaging was performed in treatment position for 10 patients with prostate cancer undergoing intensity-modulated radiotherapy (340 fraction CTs). Applied fraction doses were recalculated on daily images, and voxel-wise dose accumulation was performed using a deformable registration algorithm. For weekly imaging, weekly position correction vectors were derived and used to rigidly register daily scans of that week to the planning CT scan prior to dose accumulation. Applied and prescribed doses were compared in dependence of the imaging frequency, and derived TCP and NTCP values were calculated. Results: Daily CT-based repositioning resulted in non-significant deviations of all analyzed dose-volume, conformity and uniformity parameters to the CTV, bladder and rectum irrespective of anatomic changes. Derived average TCP values were comparable, and NTCP values for the applied doses to the bladder and rectum did not significantly deviate from the planned values. For weekly imaging, the applied D2 to the CTV, rectum and bladder significantly varied from the planned doses, and the CTV conformity index and D98 decreased. While TCP values were comparable, the NTCP for the bladder erroneously appeared reduced for weekly repositioning. Conclusions: Based on daily diagnostic quality CT imaging and voxel-wise dose accumulation, we demonstrated for the first time that daily, but not weekly imaging resulted in only negligible deviations of the applied from the planned doses for prostate intensity-modulated radiotherapy. Therefore, weekly imaging may not be adequately reliable for adaptive treatment delivery techniques for prostate. This work will contribute to devising adaptive re-planning strategies for prostate radiotherapy.

Primary adenoid cystic carcinoma of the trachea: clinical outcome of 38 patients after interdisciplinary treatment in a single institution.

BACKGROUND: Primary adenoid cystic carcinomas (ACCs) of the trachea are rare tumors of the central bronchial system. In patients presenting with unresectable tumors, severe comorbidities, or incomplete surgical resection, definitive radiotherapy is currently the recommended treatment. Irradiation with carbon ions (C12) has shown promising local control (LC) and survival rates in cases of ACCs of the head and neck. No data on the therapeutic efficacy of C12 radiotherapy in treating tracheal ACC has been published. METHODS: All patients with histologically confirmed ACC of the trachea treated with surgery and/or radiation treatment at Heidelberg University Hospital between 1991 and 2017 were included in this analysis. Patient and treatment characteristics, short- and long-term toxicity after radiotherapy, overall survival (OS), freedom from local progression (FFLP), and freedom from distant progression (FFDP) were prospectively acquired and retrospectively analyzed. RESULTS: Thirty-eight patients (23 women and 15 men) with a median age of 51 were treated by surgery (n = 20) and/or radiotherapy with either C12 (n = 7) or photons (n = 24). Of these patients, 61% presented with locally advanced (stage 4) ACC. The median follow-up for all patients was 74.5 months. The 5-year OS for all patients was 95% (10-year: 81%). The 5-year FFLP and FFDP were 96% (10-year: 83%) and 69% (10-year: 53%), respectively. In patients who underwent surgery alone, the 5-year OS was 100% (10-year: 80%). The 5-year FFLP and FFDP were 100% (10-year: 100%) and 80% (10-year: 60%), respectively. In patients who underwent radiotherapy alone, the 5-year OS was 100% (10-year: 83%). The 5-year FFLP and FFDP were 88% (10-year: 44%) and 67% (10-year: 34%), respectively. In patients who received multi-modal treatment including surgery and adjuvant radiotherapy, the 5-year OS was 84% (10-year: 84%). The 5-year FFLP was 100% (10-year: 100%) and the 5-year FFDP was 65% (10-year, 65%). CONCLUSIONS: The long-term prognosis is favorable if surgery is performed. In cases of an incomplete resection, good OS can still be achieved following adjuvant radiotherapy. For radiotherapy, irradiation with C12 shows promising first results. However, more data is needed to prove the long-term advantage of C12 over photons. TRIAL REGISTRATION: The ethics committee of the Heidelberg University Hospital approved the retrospective data analysis (S-174/2019).