Multicenter analysis on the value of standard (chemo)radiotherapy in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction.

BACKGROUND: To assess the tolerability and oncological results of chemoradiation in elderly patients with locally advanced adenocarcinoma of the esophagus or gastroesophageal junction. METHODS: This multi-center retrospective analysis included 86 elderly patients (≥ 65 years) with esophageal or gastroesophageal junction adenocarcinoma (median age 73 years; range 65-92 years) treated with definitive or neoadjuvant (chemo)radiotherapy. The treatment was performed at 3 large comprehensive cancer centers in Germany from 2006 to 2020. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities according to CTCAE criteria v5.0 were analyzed, and parameters potentially relevant to patient outcomes were evaluated. RESULTS: Thirty-three patients (38%) were treated with neoadjuvant chemoradiation followed by surgery, while the remaining patients received definitive (chemo)radiation. The delivery of radiotherapy without dose reduction was possible in 80 patients (93%). In 66 patients (77%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 48% of patients (n = 32) required chemotherapy de-escalation due to treatment-related toxicities and comorbidities. Twenty-nine patients (34%) experienced higher-grade acute toxicities and 14 patients (16%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS amounted to 72%, 49%, 46%, and 52%, respectively. In multivariate analysis, neoadjuvant chemoradiation followed by surgery was shown to be associated with significantly better PFS (p = 0.006), DMFS (p = 0.006), and OS (p = 0.004) compared with all non-surgical treatments (pooled definitive radiotherapy and chemoradiation). No such advantage was seen over definitive chemoradiation. The majority of patients with neoadjuvant therapy received standard chemoradiotherapy without dose reduction (n = 24/33, 73%). In contrast, concurrent chemotherapy was only possible in 62% of patients undergoing definitive radiotherapy (n = 33/53), and most of these patients required dose-reduction or modification of chemotherapy (n = 23/33, 70%). CONCLUSIONS: In our analysis, omission of chemotherapy or adjustment of chemotherapy dose during definitive radiotherapy was necessary for the overwhelming majority of elderly esophageal cancer patients not eligible for surgery, and hence resulted in reduced PFS and OS. Therefore, optimization of non-surgical approaches and the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly patients with (gastro)esophageal adenocarcinoma is required.

Excellent long-term pain response and local control following postoperative radiotherapy in patients with multiple myeloma.

PURPOSE: Multiple myeloma is associated with osteolytic bone lesions, often requiring surgery of the spine and postoperative radiotherapy (RT). Although common, data for clinical and informed decision-making are sparse. In this monocentric retrospective study, we aim to report the outcome of patients who underwent spinal surgery and postoperative RT due to multiple myeloma. METHODS: A total of 54 patients with multiple myeloma who underwent prior spinal surgery and postoperative RT at our institution between 2009 and 2020 were analyzed. Spinal instability neoplastic score (SINS) and Bilsky score, posttherapeutic adverse events, clinical data, and outcomes were collected and analyzed. The primary endpoint of this study was overall survival (OS), secondary endpoints were progression-free survival (PFS), pain response, local control, and skeletal-related events (SRE). RESULTS: The 3­ and 5­year overall survival (OS) was 74.9% (95% confidence interval [CI]: 63.5-88.4%) and 58% (95% CI: 44.5-75.6%), respectively. Median survival was not reached and 75% survival was 34.3 months (95% CI: 28.7-95.4 months). Median follow-up was 63 months (95% CI: 49-94 months). The number of patients with good to adequate performance status (Karnofsky performance score [KPS] ≥ 70) significantly increased after surgery (p < 0.01). We observed no grade 3/4 toxicity and only 13 (24%) grade 1/2 adverse events. Two patients (4%) experienced SRE. Overall, 92% of patients reported reduced pain after radiotherapy, with 66% reporting complete pain response. There was no difference in pain response between patients with different Bilsky scores. Bisphosphonate therapy and lower Bilsky score at the start of RT were associated with improved OS in univariate analysis (all p < 0.05). Multivariate Cox regression confirmed a Bilsky score of 2 or 3 as an independent negative prognostic factor (HR 3.89; 95 CI 1.4-10.7; p < 0.01). We observed no in-field recurrences. CONCLUSION: In this study, we were able to show that the current standard of RT after spinal surgery of osteolytic lesions is safe. In addition, we observed a very low rate of SRE (4%) and no in-field recurrences, demonstrating the local efficacy of RT in multiple myeloma patients. Higher Bilsky scores were associated with worse OS in multivariate analysis, but had no effect on pain response.

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.

App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer Undergoing Radiotherapy: Results From a Prospective Randomized Controlled Trial.

BACKGROUND: Head and neck cancers (HNCs) are very common malignancies, and treatment often requires multimodal approaches, including radiotherapy and chemotherapy. Patients with HNC often display a high symptom burden, both due to the disease itself and the adverse effects of the multimodal therapy. Close telemonitoring of symptoms and quality of life during the course of treatment may help to identify those patients requiring early medical support. OBJECTIVE: The App-Controlled Treatment Monitoring and Support for Patients With Head and Neck Cancer (APCOT) trial aimed to investigate the feasibility of integrating electronic patient-reported outcomes (ePROs) in the treatment surveillance pathway of patients with HNC during the course of their radiotherapy. Additionally, the influence of app-based ePRO monitoring on global and disease-specific quality of life and patient satisfaction with treatment was assessed. METHODS: Patients undergoing radiotherapy for histologically proven HNCs at the Department of Radiation Oncology, University Medical Center Freiburg, Germany, were enrolled in this trial and monitored by weekly physician appointments. Patients were randomized between additional ePRO monitoring on each treatment day or standard-of-care monitoring. Feasibility of ePRO monitoring was defined as ≥80% of enrolled patients answering ≥80% of their daily app-based questions. Quality of life and patient satisfaction were assessed by the European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire (QLQ-C30), the head and neck cancer module (H&N35), and the validated Patient Satisfaction Questionnaire Short Form (PSQ-18) at the completion of treatment and compared between trial arms. RESULTS: A total of 100 patients were enrolled in this trial, and 93 patients were evaluable. All patients (100%) in the experimental arm answered ≥80% of the ePRO questions during treatment, reaching the predefined threshold for the feasibility of ePRO monitoring (P<.001 in the binomial test). No clinical or patient-specific factor was found to influence feasibility. Global health and most domains of the general quality of life were comparable between trial arms, but an increased HNC-specific symptom burden was reported by patients undergoing ePRO surveillance. ePRO monitoring resulted in improved patient satisfaction regarding interpersonal manners (P=.01), financial aspects (P=.01), and time spent with a doctor (P=.01). CONCLUSIONS: This trial demonstrated the feasibility of incorporating daily app-based ePRO surveillance for patients with HNC undergoing radiotherapy. Our data, for the first time, demonstrate that telemonitoring in this setting led to increased reporting of HNC-specific symptom burden and significantly improved several domains of patient satisfaction. Further analyses are needed to assess whether our findings hold true outside the context of a clinical trial. TRIAL REGISTRATION: German Clinical Trials Register DRKS00020491; https://drks.de/search/en/trial/DRKS00020491.

Chemoradiotherapy in geriatric patients with squamous cell carcinoma of the esophagus: Multi-center analysis on the value of standard treatment in the elderly.

Background and purpose: To evaluate the tolerability and outcomes of chemoradiation in elderly patients with locally advanced esophageal squamous cell carcinoma (ESCC). Materials and methods: This multi-center retrospective analysis included 161 patients with SCC of the esophagus with a median age of 73 years (range 65-89 years) treated with definitive or neoadjuvant (chemo)radiotherapy between 2010 and 2019 at 3 large comprehensive cancer centers in Germany. Locoregional control (LRC), progression-free survival (PFS), distant metastasis-free survival (DMFS), overall survival (OS), and treatment-associated toxicities were analyzed, and parameters determining patient outcomes and treatment tolerance were assessed. Results: The delivery of radiotherapy without dose reduction was possible in 149 patients (93%). In 134 patients (83%), concomitant chemotherapy was initially prescribed; however, during the course of therapy, 41% of these patients (n = 55) required chemotherapy de-escalation due to treatment-related toxicities. Fifty-two patients (32%) experienced higher-grade acute toxicities, and 22 patients (14%) higher-grade late toxicities. The 2-year LRC, DMFS, PFS, and OS rates amounted to 67.5%, 33.8%, 31.4%, and 40.4%, respectively. Upon multivariate analysis, full-dose concomitant chemotherapy (vs. no or modified chemotherapy) was associated with significantly better DMFS (p=0.005), PFS (p=0.005) and OS (p=0.001). Furthermore, neoadjuvant chemoradiotherapy followed by tumor resection (vs. definitive chemoradiotherapy or definitive radiotherapy alone) significantly improved PFS (p=0.043) and OS (p=0.049). We could not identify any clinico-pathological factor that was significantly associated with LRC. Furthermore, definitive (chemo)radiotherapy, brachytherapy boost and stent implantation were significantly associated with higher-grade acute toxicities (p<0.001, p=0.002 and p=0.04, respectively). The incidence of higher-grade late toxicities was also significantly associated with the choice of therapy, with a higher risk for late toxicities when treatment was switched from neoadjuvant to definitive (chemo)radiotherapy compared to primary definitive (chemo)radiotherapy (p<0.001). Conclusions: Chemoradiation with full-dose and unmodified concurrent chemotherapy has a favorable prognostic impact in elderly ESCC patients; however, about half of the analyzed patients required omission or adjustment of chemotherapy due to comorbidities or toxicities. Therefore, the identification of potential predictive factors for safe administration of concurrent chemotherapy in elderly ESCC patients requires further exploration to optimize treatment in this vulnerable patient cohort.

Changes in Blood Biomarkers of Angiogenesis and Immune Modulation after Radiation Therapy and Their Association with Outcomes in Thoracic Malignancies.

The effects of radiotherapy on systemic immunity remain to be fully characterized in a disease-specific manner. The aim of the study was to examine potential biomarkers of systemic immunomodulation when using radiotherapy for thoracic malignancies. Serial blood samples were collected from 56 patients with thoracic malignancies prior (RTbaseline), during (RTduring) and at the end of radiotherapy (RTend), as well as at the first (FU1) and second follow-up (FU2). The changes in serum levels of IL-10, IFN-γ, IL-12p70, IL-13, IL-1ß, IL-4, IL-6, IL-8, TNF-α, bFGF, sFlt-1, PlGF, VEGF, VEGF-C, VEGF-D and HGF were measured by multiplexed array and tested for associations with clinical outcomes. We observed an increase in the levels of IL-10, IFN-γ, PlGF and VEGF-D and a decrease in those of IL-8, VEGF, VEGF-C and sFlt-1 during and at the end of radiotherapy. Furthermore, baseline concentration of TNF-α significantly correlated with OS. IL-6 level at RTend and FU1,2 correlated with OS (RTend: p = 0.039, HR: 1.041, 95% CI: 1.002-1.082, FU1: p = 0.001, HR: 1.139, 95% CI: 1.056-1.228, FU2: p = 0.017, HR: 1.101 95% CI: 1.018-1.192), while IL-8 level correlated with OS at RTduring and RTend (RTduring: p = 0.017, HR: 1.014, 95% CI: 1.002-1.026, RTend: p = 0.004, HR: 1.007, 95% CI: 1.061-1.686). In conclusion, serum levels of TNF-α, IL-6 and IL-8 are potential biomarkers of response to radiotherapy. Given the recent implementation of immunotherapy in lung and esophageal cancer, these putative blood biomarkers should be further validated and evaluated in the combination or sequential therapy setting.

Innovative radiation oncology Together - Precise, Personalized, Human : Vision 2030 for radiotherapy & radiation oncology in Germany.

PURPOSE: Scientific and clinical achievements in radiation, medical, and surgical oncology are changing the landscape of interdisciplinary oncology. The German Society for Radiation Oncology (DEGRO) working group of young clinicians and scientists (yDEGRO) and the DEGRO representation of associate and full professors (AKRO) are aware of the essential role of radiation oncology in multidisciplinary treatment approaches. Together, yDEGRO and AKRO endorsed developing a German radiotherapy & radiation oncology vision 2030 to address future challenges in patient care, research, and education. The vision 2030 aims to identify priorities and goals for the next decade in the field of radiation oncology. METHODS: The vision development comprised three phases. During the first phase, areas of interest, objectives, and the process of vision development were defined jointly by the yDEGRO, AKRO, and the DEGRO board. In the second phase, a one-day strategy retreat was held to develop AKRO and yDEGRO representatives' final vision from medicine, biology, and physics. The third phase was dedicated to vision interpretation and program development by yDEGRO representatives. RESULTS: The strategy retreat's development process resulted in conception of the final vision "Innovative radiation oncology Together - Precise, Personalized, Human." The first term "Innovative radiation oncology" comprises the promotion of preclinical research and clinical trials and highlights the development of a national committee for strategic development in radiation oncology research. The term "together" underpins collaborations within radiation oncology departments as well as with other partners in the clinical and scientific setting. "Precise" mainly covers technological precision in radiotherapy as well as targeted oncologic therapeutics. "Personalized" emphasizes biology-directed individualization of radiation treatment. Finally, "Human" underlines the patient-centered approach and points towards the need for individual longer-term career curricula for clinicians and researchers in the field. CONCLUSION: The vision 2030 balances the ambition of physical, technological, and biological innovation as well as a comprehensive, patient-centered, and collaborative approach towards radiotherapy & radiation oncology in Germany.

Efficacy of Stereotactic Body Radiotherapy in Patients With Hepatocellular Carcinoma Not Suitable for Transarterial Chemoembolization (HERACLES: HEpatocellular Carcinoma Stereotactic RAdiotherapy CLinical Efficacy Study).

The aim of this prospective observational trial was to evaluate the efficacy, toxicity and quality of life after stereotactic body radiation therapy (SBRT) in patients with hepatocellular carcinoma (HCC) and to assess the results of this treatment in comparison to trans-arterial chemoembolization (TACE). Patients with HCC, treated with TACE or SBRT, over a period of 12 months, enrolled in the study. The primary endpoint was feasibility; secondary endpoints were toxicity, quality of life (QOL), local progression (LP) and overall survival (OS). Between 06/2016 and 06/2017, 19 patients received TACE and 20 SBRT, 2 of whom were excluded due to progression. The median follow-up was 31 months. The QOL remained stable before and after treatment and was comparable in both treatment groups. Five patients developed grade ≥ 3 toxicities in the TACE group and 3 in the SBRT group. The cumulative incidence of LP after 1-, 2- and 3-years was 6, 6, 6% in the SBRT group and 28, 39, and 65% in the TACE group (p = 0.02). The 1- and 2- years OS rates were 84% and 47% in the TACE group and 44% and 39% in the SBRT group (p = 0.20). In conclusion, SBRT is a well-tolerated local treatment with a high local control rates and can be safely delivered, while preserving the QOL of HCC patients.

App-Controlled Treatment Monitoring and Support for Head and Neck Cancer Patients (APCOT): Protocol for a Prospective Randomized Controlled Trial.

BACKGROUND: Head and neck cancers (HNCs) are among the most common malignancies, which often require multimodal treatment that includes radiation therapy and chemotherapy. Patients with HNC have a high burden of symptoms due to both the damaging effects of the tumor and the aggressive multimodal treatment. Close symptom monitoring over the course of the disease may help to identify patients in need of medical interventions. OBJECTIVE: This APCOT (App-Controlled Treatment Monitoring and Support for Head and Neck Cancer Patients) trial is designed to assess the feasibility of monitoring HNC patients during the course of (chemo)radiation therapy daily using a mobile app. Additionally, symptom patterns, patient satisfaction, and quality of life will be measured in app-monitored patients in comparison to a patient cohort receiving standard-of-care physician appointments, and health economy aspects of app monitoring will be analyzed. METHODS: This prospective randomized single-center trial will evaluate the feasibility of integrating electronic patient-reported outcome measures (ePROMs) into the treatment workflow of HNC patients. Patients undergoing definitive or adjuvant (chemo)radiation therapy as part of their HNC treatment at the Department of Radiation Oncology, University Medical Center Freiburg (Freiburg, Germany) will receive weekly physician appointments and additional appointments as requested to monitor and potentially treat symptoms during the course of treatment. Patients in the experimental arm will additionally be monitored daily using a dedicated app regarding their disease- and treatment-related symptoms, quality of life, and need for personal physician appointments. The feasibility of ePROM monitoring will be tested as the primary endpoint and will be defined if ≥80% of enrolled patients have answered ≥80% of their daily app-based questions. Quality of life will be assessed using the validated European Organisation for Research and Treatment of Cancer questionnaires, and patient satisfaction will be measured by the validated Patient Satisfaction Questionnaire Short Form at the initiation, in the middle, and at completion of radiation therapy, as well as at follow-up examinations. Additionally, the number and duration of physician appointments during the course of radiation therapy will be quantified for both ePROM-monitored and standard-of-care patients. RESULTS: This trial will enroll 100 patients who will be randomized (1:1) between the experimental arm with ePROM monitoring and the control arm with standard patient care. Recruitment will take 18 months, and trial completion is planned at 24 months after enrollment of the last patient. CONCLUSIONS: This trial will establish the feasibility of close ePROM monitoring of HNC patients undergoing (chemo)radiation therapy. The results can form the basis for further trials investigating potential clinical benefits of detailed symptom monitoring and patient-centered care in HNC patients regarding oncologic outcomes and quality of life. TRIAL REGISTRATION: German Clinical Trials Register DRKS00020491; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00020491. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/21693.

High-dose carbon-ion based radiotherapy of primary and recurrent sacrococcygeal chordomas: long-term clinical results of a single particle therapy center.

BACKGROUND: This study aimed to analyze the oncological long-term results and late toxicity of carbon ion-based radiotherapy (RT) of patients with sacral chordoma and to identify potential prognostic factors for local control (LC) and overall survival (OS). METHODS: A total of 68 patients with sacral chordoma treated at the Heidelberg Ion Beam Therapy Center were included in this study. Of these 52 patients (77%) received a primary RT and 16 patients (23%) received a RT in a recurrent situation. All patients were treated with carbon ion RT (CIRT), either in combination with photons (n = 22; 32%) or as a monotherapy (n = 46; 68%), with a median radiation dose of 66 Gy RBE (range 60-74 Gy). In 40 patients (59%), RT was performed in the postoperative situation. Postoperative care included regular MRI scans. Local progression was defined as an enlargement of the maximum tumor diameter by 10% or a new tumor growth within the planning target volume (PTV). LC and OS were determined using the Kaplan-Meier method. Furthermore, the relevance of various prognostic factors for LC and OS was assessed by univariate and multivariate analysis. RESULTS: The median follow-up period was 60 months (range 1.3-97.4 months). The 5-year rates for LC, progression-free survival, metastasis-free survival and OS were 53, 53, 52 and 74%, respectively. Local recurrence was observed in 31 patients (46%), occurring after a median follow-up time of 25 months (range 2.5-73.1 months). Only 10% of local recurrences occurred later than 5 years after RT. Statistical analysis showed that RT in the relapse situation corresponded to inferior LC rates compared to the primary situation, while other factors such as the GTV, radiation dose (EQD2) and treatment approach (CIRT alone vs. CIRT combined with photons) were insignificant. For OS after RT, patient age and PTV size proved to be significant predictors. The incidence of late toxicity ≥ III° according to CTCAE v5.0 was 21%. Sacral insufficiency fractures occurred in 49% of patients (maximum III°: 16%) and were thus by far the most frequent late side effect in our analysis. Radiogenic damage to the peripheral nerves, intestinal tract and skin was observed in only 9% (≥ III°: 5%), 3% (all II°) and 9% (all I°) of patients. CONCLUSION: Our analysis showed only moderate long-term LC rates after carbon ion-based RT, with sacral chordomas having a particularly poor prognosis in the recurrent situation. Therefore, future studies should evaluate the safety and effectiveness of further dose escalation and hypofractionation of RT in sacral chordoma and weight potential benefits of dose escalation against side effects.

The Value of Laboratory Parameters for Anemia, Renal Function, Systemic Inflammation and Nutritional Status as Predictors for Outcome in Elderly Patients with Head-and-Neck Cancers.

The purpose of this study was to evaluate the value of routine blood markers regarding their predictive potential for treatment outcomes of elderly head-and-neck squamous cell carcinoma (HNSCC) patients. In total, 246 elderly HNSCC patients (≥65 years) undergoing (chemo)radiotherapy from 2010 to 2018 were analyzed for treatment outcomes, depending on their hemoglobin, glomerular filtration rate (GFR), C-reactive protein (CRP) and albumin values, representing anemia, kidney function, inflammation and nutrition status, respectively. Local/locoregional control, progression-free and overall survival (OS) were calculated using the Kaplan-Meier method. Cox analyses were performed to examine the influence of blood parameters on oncological outcomes. In the univariate Cox regression analysis, hemoglobin ≤ 12 g/dL (HR = 1.536, p < 0.05), a GFR ≤ 60 mL/min/1.73 m2 (HR = 1.537, p < 0.05), a CRP concentration > 5 mg/L (HR = 1.991, p < 0.001) and albumin levels ≤ 4.2 g/dL (HR = 2.916, p < 0.001) were significant risk factors for OS. In the multivariate analysis including clinical risk factors, only performance status (HR = 2.460, p < 0.05) and baseline albumin (HR = 2.305, p < 0.05) remained significant prognosticators. Additionally, baseline anemia correlated with the prevalence of higher-grade chronic toxicities. We could show for the first time that laboratory parameters for anemia (and at least partly, tumor oxygenation), decreased renal function, inflammation and reduced nutrition status are associated with impaired survival in elderly HNSCC patients undergoing (chemo)radiotherapy.

The Role of Palliative Radiotherapy in the Treatment of Spinal Bone Metastases from Head and Neck Tumors-A Multicenter Analysis of a Rare Event.

This retrospective multi-center analysis aimed to assess the clinical response and stabilizing effects of palliative radiotherapy (RT) for spinal bone metastases (SBM) in head and neck cancer (HNC), and to establish potential predictive factors for stability and overall survival (OS). Patients included in this analysis were treated at the University Hospitals of Mainz, Freiburg, and Heidelberg between 2001 and 2019. Clinical information was taken from the medical records. The stability of affected vertebral bodies was assessed according to the validated spine instability neoplastic score (SINS) based on CT-imaging before RT, as well as 3 and 6 months after RT. OS was quantified as the time between the start of palliative RT and death from any cause or last follow-up. Potential predictive factors for stability and OS were analyzed using generalized estimating equations and Cox regression for time-varying covariates to take into account multiple observations per patient. The mean follow-up time of 66 included patients after the first palliative RT was 8.1 months (range 0.3-85.0 months). The majority of patients (70%; n = 46) had squamous cell carcinomas (SCC) originating from the pharynx, larynx and oral cavity, while most of the remaining patients (26%; n = 17) suffered from salivary glands tumors. A total of 95 target volumes including 178 SBM were evaluated that received a total of 81 irradiation series. In patients with more than one metastasis per irradiated region, only the most critical bone metastasis was analyzed according to the SINS system. Prior to RT, pain and neurologic deficits were present in 76% (n = 72) and 22% (n = 21) of irradiated lesions, respectively, and 68% of the irradiated lesions (n = 65) were assessed as unstable or potentially unstable prior to RT. SBM-related pain symptoms and neurologic deficits responded to RT in 63% and 47% of the treated lesions, respectively. Among patients still alive at 3 and 6 months after RT with potentially unstable or unstable SBM, a shift to a better stability class according to the SINS was observed in 20% and 33% of the irradiated SBM, respectively. Pathological fractures of SBM were frequently detected before the start of irradiation (43%; n = 41), but after RT, new fractures or increasing vertebral body sintering within the irradiated region occurred rarely (8%; n = 8). A pathological fracture before RT was negatively associated with stabilization 6 months after RT (OR 0.1, 95% CI 0.02-0.49, p = 0.004), while a Karnofsky performance score (KPS) ≥ 70% was associated positively with a stabilization effect through irradiation (OR 6.09, 95% CI 1.68-22.05, p = 0.006). Mean OS following first palliative RT was 10.7 months, and the KPS (≥70% vs. <70%) was shown to be a strong predictive factor for OS after RT (HR 0.197, 95% CI 0.11-0.35, p < 0.001). There was no significant difference in OS between patients with SCC and non-SCC. Palliative RT in symptomatic SBM of HNC provides sufficient symptom relief in the majority of patients, while only about one third of initially unstable SBM show re-stabilization after RT. Since patients in our multi-center cohort exhibited very limited OS, fractionation schemes should be determined depending on the patients' performance status.

Convolutional neural networks for head and neck tumor segmentation on 7-channel multiparametric MRI: a leave-one-out analysis.

BACKGROUND: Automatic tumor segmentation based on Convolutional Neural Networks (CNNs) has shown to be a valuable tool in treatment planning and clinical decision making. We investigate the influence of 7 MRI input channels of a CNN with respect to the segmentation performance of head&neck cancer. METHODS: Head&neck cancer patients underwent multi-parametric MRI including T2w, pre- and post-contrast T1w, T2*, perfusion (ktrans, ve) and diffusion (ADC) measurements at 3 time points before and during radiochemotherapy. The 7 different MRI contrasts (input channels) and manually defined gross tumor volumes (primary tumor and lymph node metastases) were used to train CNNs for lesion segmentation. A reference CNN with all input channels was compared to individually trained CNNs where one of the input channels was left out to identify which MRI contrast contributes the most to the tumor segmentation task. A statistical analysis was employed to account for random fluctuations in the segmentation performance. RESULTS: The CNN segmentation performance scored up to a Dice similarity coefficient (DSC) of 0.65. The network trained without T2* data generally yielded the worst results, with ΔDSCGTV-T = 5.7% for primary tumor and ΔDSCGTV-Ln = 5.8% for lymph node metastases compared to the network containing all input channels. Overall, the ADC input channel showed the least impact on segmentation performance, with ΔDSCGTV-T = 2.4% for primary tumor and ΔDSCGTV-Ln = 2.2% respectively. CONCLUSIONS: We developed a method to reduce overall scan times in MRI protocols by prioritizing those sequences that add most unique information for the task of automatic tumor segmentation. The optimized CNNs could be used to aid in the definition of the GTVs in radiotherapy planning, and the faster imaging protocols will reduce patient scan times which can increase patient compliance. TRIAL REGISTRATION: The trial was registered retrospectively at the German Register for Clinical Studies (DRKS) under register number DRKS00003830 on August 20th, 2015.

Impact of a low FODMAP diet on the amount of rectal gas and rectal volume during radiotherapy in patients with prostate cancer - a prospective pilot study.

BACKGROUND: Small inter- and intrafractional prostate motion was shown to be a prerequisite for precise radiotherapy (RT) of prostate cancer (PCa) to achieve good local control and low rectal toxicity. As rectal gas and rectal volume are known to have a relevant effect on prostate motion, this study aims to reduce these parameters by using a Low FODMAP Diet (LFD) and to show feasibility of this intervention. METHODS: We compared a prospective intervention group (IG, n = 25) which underwent RT for PCa and whose patients were asked to follow a LFD during RT with a retrospective control group (CG, n = 25) which did not get any dietary advice. In the planning CT scan and all available cone beam CT scans rectal gas was classified based on a semiquantitative score (scale from 1 to 5) and rectal volume was measured. Furthermore, patients' compliance was evaluated by a self-assessment questionnaire. RESULTS: Clinical and treatment characteristics were well balanced between both groups. A total of 266 (CG, 10.6 per patient) and 280 CT scans (IG, 11.2 per patient), respectively, were analysed. The frequency distribution of gas scores differed significantly from each other (p < .001) with the IG having lower scores. Rectal volume was smaller in the IG (64.28 cm3, 95% CI 60.92-67.65 cm3, SD 28.64 cm3) than in the CG (71.40 cm3, 95% CI 66.47-76.32 cm3, SD 40.80 cm3) (p = .02). Mean intrapatient standard deviation as a measure for the variability of rectal volume was 22 cm3 in the IG and 23 cm3 in the CG (p = .81). Patients' compliance and contentment were satisfying. CONCLUSIONS: The use of a LFD significantly decreased rectal gas and rectal volume. LFD was feasible with an excellent patients' compliance. However, prospective trials with a larger number of patients and a standardized evaluation of gastrointestinal toxicity and quality of life are reasonable. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00012955. Registered 29 August 2017 - Retrospectively registered, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00012955.

Resection of recurrent glioblastoma multiforme in elderly patients: a pseudo-randomized analysis revealed clinical benefit.

INTRODUCTION: Elderly patients constitute an expanding part of our society. Due to a continuously increasing life expectancy, an optimal quality of life is expected even into advanced age. Glioblastoma (GBM) is more common in older patients, but they are still often withheld from efficient treatment due to worry of worse tolerance and have a significantly worse prognosis compared to younger patients. Our retrospective observational study aimed to investigate the therapeutic benefit from a second resection in recurrent glioblastoma of elderly patients. MATERIALS AND METHODS: We included a cohort of 39 elderly patients (> 65 years) with a second resection as treatment option in the case of a tumor recurrence. A causal inference model was built by multiple non- and semiparametric models, which was used to identify matched patients from our elderly GBM database which comprises 538 patients. The matched cohorts were analyzed by a Cox-regression model adjusted by time-dependent covariates. RESULTS: The Cox-regression analysis showed a significant survival benefit (Hazard Ratio: 0.6, 95% CI 0.36-0.9, p-value = 0.0427) for the re-resected group (18.0 months, 95% CI 13.97-23.2 months) compared to the group without re-resection (10.1 months, 95% CI 8.09-20.9 months). No differences in the co-morbidities or hemato-oncological side effects during chemotherapy could be detected. Anesthetic- and surgical complications were rare and comparable to the complication rate of patients undergoing the first-line resection. CONCLUSION: Taken together, in elderly patients, re-resection is an acceptable treatment option in the recurrent state of a glioblastoma. The individual evaluation of the patients' medical status as well as the chances of withstanding general anesthesia needs to be done in close interdisciplinary consultation. If these requirements are met, elderly patients benefit from a re-resection.

Real-time 4DMRI-based internal target volume definition for moving lung tumors.

PURPOSE: In photon radiotherapy, respiratory-induced target motion can be accounted for by internal target volumes (ITV) or mid-ventilation target volumes (midV) defined on the basis of four-dimensional computed tomography (4D-CT). Intrinsic limitations of these approaches can result in target volumes that are not representative for the gross tumor volume (GTV) motion over the course of treatment. To address these limitations, we propose a novel patient-specific ITV definition method based on real-time 4D magnetic resonance imaging (rt-4DMRI). METHODS: Three lung cancer patients underwent weekly rt-4DMRI scans. A total of 24 datasets were included in this retrospective study. The GTV was contoured on breath-hold MR images and propagated to all rt-4DMRI images by deformable image registration. Different targets were created for the first (reference) imaging sessions: ITVs encompassing all GTV positions over the complete (ITV 80 s ) or partial acquisition time ( ITV 10 s ), ITVs including only voxels with a GTV probability-of-presence (POP) of at least 5% ( ITV 5 % ) or 10% ( ITV 10 % ), and the mid-ventilation GTV position. Reference planning target volumes ( PTV r ) were created by adding margins around the ITVs and midV target volumes. The geometrical overlap of the PTV r with ITV n 5 % from the six to eight subsequent imaging sessions on days n was quantified in terms of the Dice similarity coefficient (DSC), sensitivity [SE: ( PTV r ∩ ITV n 5 % )/ ITV n 5 % ] and precision [PRE: ( PTV r ∩ ITV n 5 % )/ PTV r ] as surrogates for target coverage and normal tissue sparing. RESULTS: Patient-specific analysis yielded a high variance of the overlap values of PTV r 10 s , when different periods within the reference imaging session were sampled. The mid-ventilation-based PTVs were smaller than the ITV-based PTVs. While the SE was high for patients with small breathing pattern variations, changes of the median breathing amplitudes in different imaging sessions led to inferior SE values for the mid-ventilation PTV for one patient. In contrast, PTV r 5 % and PTV r 10 % showed higher SE values with a higher robustness against interfractional changes, at the cost of larger target volumes. CONCLUSIONS: The results indicate that rt-4DMRI could be valuable for the definition of target volumes based on the GTV POP to achieve a higher robustness against interfractional changes than feasible with today's 4D-CT-based target definition concepts.

Paravertebral Muscle Training in Patients with Unstable Spinal Metastases Receiving Palliative Radiotherapy: An Exploratory Randomized Feasibility Trial.

Background: Isometric paravertebral muscle training (IPMT) may improve mobility, pain, and quality of life (QOL) in cancer patients with spinal metastases. However, this regimen remains unproven in patients with unstable spinal metastases (USM), a population at high risk for clinical exacerbation with such interventions. Thus, we conducted this exploratory, non-blinded, randomized controlled trial (NCT02847754) to evaluate the safety/feasibility of IPMT and secondarily assess pain, bone density, pathologic fracture rate, and QOL. Methods: All patients had histologically/radiologically confirmed USM (per Taneichi score) and underwent non-operative management with 5-10 fractions of palliative radiotherapy (RT). Randomization (1:1) groups were IPMT (intervention, INT) or muscle relaxation (control, CON); both lasted 15 min/day and started concurrently with radiotherapy. The primary endpoint was feasibility (completion of training programs three months post-RT). Secondary endpoints were pain response (Visual Analog Scale) and opioid consumption, bone density and pathologic fracture rate, and QOL (European Organization for Research and Treatment of Cancer, EORTC questionnaires). Results: Sixty patients were randomized and 56 received protocol therapy. Mean survival in both groups was 4.4 months. There were no adverse events with either training regimen. Altogether, ≥80% of the planned sessions were completed by 55% (n = 16/29) in CON and 67% (n = 18/27) in INT. Regarding the post-radiotherapy home-based training, ≥80% of planned sessions were completed by 64% (n = 9/14) of the INT cohort. There were no differences in pain scores, opioid consumption, or bone density between arms (p > 0.05 for all). No difference was observed between groups regarding new pathological fractures (INT: n = 1 vs. CON: n = 3) after three months (p = 0.419). There were no QOL differences between arms (all parameters p > 0.05). Conclusions: IPMT is potentially feasible for high-risk USM patients. Future trials adequately powered for relevant endpoints are thus recommended.

Automatic Tumor Segmentation With a Convolutional Neural Network in Multiparametric MRI: Influence of Distortion Correction.

Precise tumor segmentation is a crucial task in radiation therapy planning. Convolutional neural networks (CNNs) are among the highest scoring automatic approaches for tumor segmentation. We investigate the difference in segmentation performance of geometrically distorted and corrected diffusion-weighted data using data of patients with head and neck tumors; 18 patients with head and neck tumors underwent multiparametric magnetic resonance imaging, including T2w, T1w, T2*, perfusion (ktrans), and apparent diffusion coefficient (ADC) measurements. Owing to strong geometrical distortions in diffusion-weighted echo planar imaging in the head and neck region, ADC data were additionally distortion corrected. To investigate the influence of geometrical correction, first 14 CNNs were trained on data with geometrically corrected ADC and another 14 CNNs were trained using data without the correction on different samples of 13 patients for training and 4 patients for validation each. The different sets were each trained from scratch using randomly initialized weights, but the training data distributions were pairwise equal for corrected and uncorrected data. Segmentation performance was evaluated on the remaining 1 test-patient for each of the 14 sets. The CNN segmentation performance scored an average Dice coefficient of 0.40 ± 0.18 for data including distortion-corrected ADC and 0.37 ± 0.21 for uncorrected data. Paired t test revealed that the performance was not significantly different (P = .313). Thus, geometrical distortion on diffusion-weighted imaging data in patients with head and neck tumor does not significantly impair CNN segmentation performance in use.

Carbon-ion irradiation overcomes HPV-integration/E2 gene-disruption induced radioresistance of cervical keratinocytes.

To date, only few data exist on mechanisms underlying the human papillomavirus (HPV)-associated irradiation response. It has been suggested, that the viral E2 gene plays an important role in that context. The aim of the current study is to compare the effect of photon- and carbon-ion (12C)-radiation therapy (RT) on cells with different HPV and E2 gene status. We hypothesized that 12C-RT might overcome the radioresistance of E2 gene-disrupted cells. We analyzed four different cell lines that differed in HPV status or E2 gene status. Cells were irradiated with either photons or 12C. Clonogenic survival, cell cycle and expression of Rb and p53 were analyzed. Radiosensitivity seemed to be dependent on E2 gene status and type of RT. 12C-RT led to lower surviving fractions, indicating higher radiosensitivity even in cells with disrupted E2 gene. The observed relative biological effectiveness (RBE) of 12C-RT for C33a/Caski and W12/S12 was 1.3/4 and 2.7/2.5, respectively. Cell cycle regulation after both photon- and 12C-RT was dependent on HPV status and on E2 gene status. Furthermore, the effect of RT on expression of p53 and Rb seemed to be dependent on E2 gene status and type of RT. We showed that 12C-RT overcomes HPV-integration induced radioresistance. The effect of RT on cell cycle regulation as well as on expression of p53 and Rb seemed to be dependent on HPV status, E2 gene status and type of RT. Differences in Rb expression and cell cycle regulation may play a role for enhanced radiosensitivity to 12C-RT of cells with disrupted E2 gene.