Long-term results in malignant pleural mesothelioma treated with neoadjuvant chemotherapy, extrapleural pneumonectomy and intensity-modulated radiotherapy

Introduction: We investigated the clinical outcome and the toxicity of trimodal therapy of malignant pleural mesothelioma (MPM) treated with neoadjuvant chemotherapy, extrapleural pneumonectomy (EPP) and adjuvant intensity-modulated radiotherapy (IMRT). Methods: Chemotherapy regimens included Cisplatin/Pemetrexed, Carboplatin/Pemetrexed and Cisplatin/Gemcitabine, followed by EPP. 62 patients completed the adjuvant radiotherapy. IMRT was carried out in two techniques, either step&shoot or helical tomotherapy. Median target dose was 48 Gy to 54 Gy. Toxicity was scored with the Common Terminology Criteria (CTC) for Adverse Events. We used Kaplan-Meier method to estimate actuarial rate of locoregional control (LRC),distant control (DC) and overall survival (OS),measured from the date of surgery. Rates were compared using the logrank test. For multivariate analysis the Cox proportional hazard model was used. Results: The median OS, LRC and DC times were 20.4, 31.4 and 21.4 months. The 1-,2-,3-year OS rates were 63, 42, 28 %,the LRC rates were 81, 60, 40 %,and the DC rates were 62, 48, 41 %. We observed no CTC grade 4 or grade 5 toxicity. Step&shoot and helical tomotherapy were equivalent both in dosimetric characteristics and clinical outcome. Biphasic tumor histology was associated with worse clinical outcome compared to epitheloid histology. Conclusions: Mature clinical results of trimodal treatment for MPM were presented. They indicate that hemithoracic radiotherapy after EPP can be safely administered by either step&shoot IMRT and tomotherapy. However, the optimal prospective patient selection for this aggressive trimodal therapy approach remains unclear. This study can serve as a benchmark for current and future therapy concepts for MPM

Intensity modulated radiotherapy (IMRT) with concurrent chemotherapy as definitive treatment of locally advanced esophageal cancer

Background: To report our experience with increased dose intensity-modulated radiation and concurrent systemic chemotherapy as definitive treatment of locally advanced esophageal cancer. Patients and methods: We analyzed 27 consecutive patients with histologically proven esophageal cancer, who were treated with increased-dose IMRT as part of their definitive therapy. The majority of patients had T3/4 and/or N1 disease (93%). Squamous cell carcinoma was the dominating histology (81%). IMRT was delivered in step-and-shoot technique in all patients using an integrated boost concept. The boost volume was covered with total doses of 56-60 Gy (single dose 2-2.14 Gy), while regional nodal regions received 50.4 Gy (single dose 1.8 Gy) in 28 fractions. Concurrent systemic therapy was scheduled in all patients and administered in 26 (96%). 17 patients received additional adjuvant systemic therapy. Loco-regional control, progression-free and overall survival as well as acute and late toxicities were retrospectively analyzed. In addition, quality of life was prospectively assessed according to the EORTC QLQs (QLQ-OG25, QLQ-H&N35 and QLQ-C30). Results: Radiotherapy was completed as planned in all but one patient (96%), and 21 patients received more than 80% of the planned concurrent systemic therapy. We observed ten locoregional failures, transferring into actuarial 1-, 2- and 3-year-locoregional control rates of 77%, 65% and 48%. Seven patients developed distant metastases, mainly to the lung (71%). The actuarial 1-, 2- and 3-year-disease free survival rates were 58%, 48% and 36%, and overall survival rates were 82%, 61% and 56%. The concept was well tolerated, both in the clinical objective examination and also according to the subjective answers to the QLQ questionnaire. 14 patients (52%) suffered from at least one acute CTC grade 3/4 toxicity, mostly hematological side effects or dysphagia. Severe late toxicities were reported in 6 patients (22%), mostly esophageal strictures and ulcerations. Severe side effects to skin, lung and heart were rare. Conclusion: IMRT with concurrent systemic therapy in the definitive treatment of esophageal cancer using an integrated boost concept with doses up to 60 Gy is feasible and yields good results with acceptable acute and late overall toxicity and low side effects to skin, lung and heart

Dosimetric Impact of the Positional Imaging Frequency for Hypofractionated Prostate Radiotherapy – A Voxel-by-Voxel Analysis

Background: To investigate deviations between planned and applied treatment doses for hypofractionated prostate radiotherapy and to quantify dosimetric accuracy in dependence of the image guidance frequency. Methods: Daily diagnostic in-room CTs were carried out in 10 patients in treatment position as image guidance for hypofractionated prostate radiotherapy. Fraction doses were mapped to the planning CTs and recalculated, and applied doses were accumulated voxel-wise using deformable registration. Non-daily imaging schedules were simulated by deriving position correction vectors from individual scans and used to rigidly register the following scans until the next repositioning before dose recalculation and accumulation. Planned and applied doses were compared regarding dose-volume indices and TCP and NTCP values in dependence of the imaging and repositioning frequency. Results: Daily image-guided repositioning was associated with only negligible deviations of analyzed dose-volume parameters and conformity/homogeneity indices for the prostate, bladder and rectum. Average CTV T did not significantly deviate from the plan values, and rectum NTCPs were highly comparable, while bladder NTCPs were reduced. For non-daily image-guided repositioning, there were significant deviations in the high-dose range from the planned values. Similarly, CTV dose conformity and homogeneity were reduced. While TCPs and rectal NTCPs did not significantly deteriorate for non-daily repositioning, bladder NTCPs appeared falsely diminished in dependence of the imaging frequency. Conclusion: Using voxel-by-voxel dose accumulation, we showed for the first time that daily image-guided repositioning resulted in only negligible dosimetric deviations for hypofractionated prostate radiotherapy. Regarding dosimetric aberrations for non-daily imaging, daily imaging is required to adequately deliver treatment

Differentiated resistance training of the paravertebral muscles in patients with unstable spinal bone metastasis under concomitant radiotherapy: study protocol for a randomized pilot trial

Background: Metastatic bone disease is a common and severe complication in patients with advanced cancer. Radiotherapy (RT) has long been established as an effective local treatment for metastatic bone disorder. This study assesses the effects of RT combined with muscle-training exercises in patients with unstable bone metastases of the spinal column from solid tumors. The primary goal of this study is to evaluate the feasibility of muscle-training exercises concomitant to RT. Secondly, quality of life, fatigue, overall and bone survival, and local control will be assessed. Methods/Design: This study is a single-center, prospective, randomized, controlled, explorative intervention study with a parallel-group design to determine multidimensional effects of a course of exercises concomitant to RT on patients who have unstable metastases of the vertebral column, first under therapeutic instruction and subsequently performed by the patients themselves independently for strengthening the paravertebral muscles. On the days of radiation treatment the patients will be given four different types of exercises to ensure even isometric muscle training of all the spinal muscles. In the control group progressive muscle relaxation will be carried out parallel to RT. The patients will be randomized into two groups: differentiated muscle training or progressive muscle relaxation with 30 patients in each group. Discussion: Despite the clinical experience that RT is an effective treatment for bone metastases, there is insufficient evidence for a positive effect of the combination with muscle-training exercises in patients with unstable bone metastases. Our previous DISPO-1 trial showed that adding muscle-training exercises to RT is feasible, whereas this was not proven in patients with an unstable spinal column. Although associated with several methodological and practical challenges, this randomized controlled trial is needed. Trial registration: ClinicalTrials.gov, identifier: NCT02847754. Registered on 27 July 2016

Differential response of esophageal cancer cells to particle irradiation

Background: Radiation therapy is a mainstay in the treatment of esophageal cancer (EC) patients, and photon radiotherapy has proved beneficial both in the neoadjuvant and the definitive setting. However, regarding the still poor prognosis of many EC patients, particle radiation employing a higher biological effectiveness may help to further improve patient outcomes. However, the influence of clinically available particle radiation on EC cells remains largely unknown. Methods: Patient-derived esophageal adenocarcinoma and squamous cell cancer lines were treated with photon and particle irradiation using clinically available proton (1H), carbon (12C) or oxygen (16O) beams at the Heidelberg Ion Therapy Center. Histology-dependent clonogenic survival was calculated for increasing physical radiation doses, and resulting relative biological effectiveness (RBE) was calculated for each radiation modality. Cell cycle effects caused by photon and particle radiation were assessed, and radiation-induced apoptosis was measured in adenocarcinoma and squamous cell EC samples by activated caspase-3 and sub-G1 populations. Repair kinetics of DNA double strand breaks induced by photon and particle radiation were investigated. Results: While both adenocarcinoma EC cell lines demonstrated increasing sensitivities for 1H, 12C and 16O radiation, the two squamous cell carcinoma lines exhibited a more heterogeneous response to photon and particle treatment; average RBE values were calculated as 1.15 for 1H, 2.3 for 12C and 2.5 for 16O irradiation. After particle irradiation, squamous cell EC samples reacted with an increased and prolonged block in G2 phase of the cell cycle compared to adenocarcinoma cells. Particle radiation resulted in an incomplete repair of radiation-induced DNA double strand breaks in both adenocarcinoma and squamous cell carcinoma samples, with the levels of initial strand break induction correlating well with the individual cellular survival after photon and particle radiation. Similarly, EC samples demonstrated heterogeneous levels of radiation-induced apoptosis that also corresponded to the observed cellular survival of individual cell lines. Conclusions: Esophageal cancer cells exhibit differential responses to irradiation with photons and 1H, 12C and 16O particles that were independent of tumor histology. Therefore, yet unknown molecular markers beyond histology may help to establish which esophageal cancer patients benefit from the biological effects of particle treatment

Moderate Dosisdeeskalation der definitiven Cisplatin-basierten Radiochemotherapie für HPV-positive Oropharynxkarzinompatienten

Purpose!#!The aim of this study was to evaluate the safety and long-term tumor control after stereotactic radiotherapy (SRT) with 12 × 6 Gy of patients with primary bronchial carcinoma (BC) or with pulmonary metastases (MET) of various solid tumors. Local progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS), and prognostic factors were compared.!##!Methods!#!Between May 2012 and January 2020, 168 patients with 206 pulmonary lesions (170 MET and 36 primary BC) were treated with 12 × 6 Gy (BED!##!Results!#!The median follow-up was 16.26 months (range: 0.46-89.34) for BC and 19.18 months (0.89-91.11) for MET. Survival rates at 3 years were: OS 43% for BC and 35% for MET; LPFS BC 96% and MET 85%; PFS BC 35% and MET 29%. The most frequently observed grade 3 adverse events (AEs) were pneumonitis (5.9% BC, 4.8% MET), pulmonary fibrosis (2.9% BC, 4% MET), and pulmonary embolism (2.9% BC, 0.8% MET). The favorable prognostic effects on overall survival of patients with MET were female gender (log-rank: p < 0.001), no systemic progression (log-rank; p = 0.048, multivariate COX regression p = 0.039), and malignant melanoma histology (log-rank; p = 0.015, multivariate COX regression p = 0.020). For patients with BC, it was tumor location within the lower lobe (vs. upper lobe, log-rank p = 0.027). LPFS of patients with metastatic disease was beneficially influenced by female gender (log-rank: p = 0.049).!##!Conclusion!#!The treatment concept of 12 × 6 Gy is associated with 96% local progression-free survival for BC and 85% for pulmonary metastases after 3 years. There was no difference in response after SRT of primary lung carcinoma or pulmonary metastases

Zirkulierende HPV-Tumor-DNA als möglicher Biomarker in der Rezidivdiagnostik des HPV-assoziierten Oropharynxkarzinoms

Background!#!Magnetic resonance imaging (MRI) and amino acid positron-emission tomography (PET) of the brain contain a vast amount of structural and functional information that can be analyzed by machine learning algorithms and radiomics for the use of radiotherapy in patients with malignant brain tumors.!##!Methods!#!This study is based on comprehensive literature research on machine learning and radiomics analyses in neuroimaging and their potential application for radiotherapy in patients with malignant glioma or brain metastases.!##!Results!#!Feature-based radiomics and deep learning-based machine learning methods can be used to improve brain tumor diagnostics and automate various steps of radiotherapy planning. In glioma patients, important applications are the determination of WHO grade and molecular markers for integrated diagnosis in patients not eligible for biopsy or resection, automatic image segmentation for target volume planning, prediction of the location of tumor recurrence, and differentiation of pseudoprogression from actual tumor progression. In patients with brain metastases, radiomics is applied for additional detection of smaller brain metastases, accurate segmentation of multiple larger metastases, prediction of local response after radiosurgery, and differentiation of radiation injury from local brain metastasis relapse. Importantly, high diagnostic accuracies of 80-90% can be achieved by most approaches, despite a large variety in terms of applied imaging techniques and computational methods.!##!Conclusion!#!Clinical application of automated image analyses based on radiomics and artificial intelligence has a great potential for improving radiotherapy in patients with malignant brain tumors. However, a common problem associated with these techniques is the large variability and the lack of standardization of the methods applied