Purpose The aim of the study is to evaluate treatment-related acute and late eye toxicity associated with radiation therapy in childhood and adolescence as correlated with RT (radiotherapy) doses. Methods From 2001 to 2016, a total of 1725 children and adolescents undergoing radiation therapy were prospectively documented in the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK). The RTOG/EORTC criteria were used to classify ocular acute and late effects. Uni- and multivariate analyses were carried out to evaluate the impact of patient age, pre-existing impairments, and radiation dose on ocular toxicity. Results Of all documented patients, 593 received dose to the eye and formed the basis of this analysis. In 435 patients, information on acute reaction was available and graded 1, 2, 3, and 4 in 49, 17, 0, and 2 patients, respectively. Information on late toxicity was available in 268 patients and graded 1, 2, 3, and 4 in 15, 11, 11, and 5 patients, respectively. The acute toxicity rate was significantly higher in children who received a maximum dose > 50 Gy to the eye ( p < 0.001) and who had a pre-existing eye impairment ( p < 0.001 in multivariate analysis). The development of late toxicity was significantly higher for patients experiencing acute toxicity and having received a radiation dose > 50 Gy. Conclusion Acute and late toxicity both correlate with high radiation dose to the eye (> 50 Gy) and acute toxicity additionally with pre-existing eye impairments.

PURPOSE:This article reports on the long-term impact of radiotherapy adapted to stage, histology, and previous resection in a large cohort of patients with intestinal lymphoma (iL) treated with definitive or adjuvant curative-intent radiation therapy (RT) ± chemotherapy (CHOP, MCP, or COP). PATIENTS AND METHODS:In two consecutive prospective study designs, 134 patients with indolent (stage IE-IIE) or aggressive (stage IE-IVE) iL were referred to 61 radiotherapeutic institutions between 1992 and 2003. Patients with indolent iL received extended field (EF) 30 Gy (+10 Gy boost in definitive treatment); patients with aggressive iL received involved field (IF) (EF) 40 Gy by means of stage-, histology-, and operation-adapted radiation fields. RESULTS:The patients had median age 58 years and were predominantly male (2:1). Histology showed aggressive prevalence (1.6:1), stage IE-to-stage IIE ratio of iL 1.04:1, and localized stages-to-advanced stages ratio of aggressive lymphoma 23:1. Median follow-up was in total 11.7 years: 10.0 years in the first study, GIT (GastroIntestinal-Tract) 1992, and 11.8 years in the second study, GIT 1996. Lymphoma involvement was predominantly a single intestinal lesion (82.1%). Decrease of radiation field size from EF to IF in stage I aggressive iL from GIT 1992 to GIT 1996 resulted in a nonsignificant partial reduction of chronic toxicity while maintaining comparable survival rates (5-year overall survival 87.9 vs. 86.7%, 10-year overall survival 77.4 vs. 71.5%) with nonsignificant difference in event-free survival (5-year event-free survival 82.6 vs. 86.7%, 10-year event-free survival 69.7 vs. 71.5%) and lymphoma-specific survival (5-year lymphoma-specific survival 90.1 vs. 91.9%, 10-year lymphoma-specific survival 87.6% vs. 91.9%). Comparative dose calculation of two still available indolent duodenal lymphoma computed tomography scans revealed lower radiation exposure to normal tissues from applying current standard involved site RT (ISRT) 30 Gy in both cases. CONCLUSION:RT adapted to stage, histology, and resection in multimodal treatment of iL, despite partially decreasing field size (EF to IF), achieves excellent local tumor control and survival rates. The use of modern RT technique and target volume with ISRT offers the option of further reduction of normal tissue complication probability. IMPLICATIONS FOR PRACTICE:Although patients with intestinal lymphoma (iL) are heterogeneous according to histology and subtype, they benefit from radiotherapy. Prospective study data from 134 patients with indolent iL (stage IE-IIE) or aggressive iL (stage IE-IVE) show 100% tumor control after definitive or adjuvant curative-intent radiation therapy ± chemotherapy. Radiation treatment was applied between 1992 and 2003. Median follow-up in total was 11.7 years. No radiotherapy-associated death occurred. Relapse developed in 15.7% of the entire cohort; distant failure was more frequent than local (4:1). Normal tissue complication probability can be further improved using modern involved site radiation therapy techniques.

To evaluate clinical, histopathologic, and radiation (RT) dose parameters in patients with extranodal low-grade (ENLG) non-Hodgkin lymphoma (NHL) and their possible impact on local control (LC) and survival. The medical records of 159 patients with 181 histologically confirmed ENLG-NHL lesions treated at our institution were reviewed retrospectively. The predominant histological subtype (73%) was marginal zone lymphoma (MZL). Common lesion sites were the gastrointestinal tract (GIT; 33%), skin (26%), and orbit (21%). The majority of patients (88%) presented with stage I/II disease. Thirty-three (20%) lesions were treated with reduced-dose RT (≤30.6 Gy) and 148 lesions (80%) with conventional-dose RT (>30.6 Gy), with an overall median dose of 39.6 Gy (range 4–63). The median follow-up period was 72 months. The 10-year local control (LC), Progression-free survival (PFS), and overall survival (OS) rates were 96, 65, and 82%, respectively. Higher overall response rate (ORR; 98% vs. 94%, p = 0.001) and complete response rate (CRR; 95% vs. 73%, p = 0.001) were observed in patients treated with conventional-dose regimens than in those treated with reduced-dose regimens. Ten-year PFS (p = 0.90) and OS (p = 0.40) was similar between the two dose groups. RT was well tolerated in both dose groups, with no grade 4/5 toxicities. In the multivariate analysis, RT dose and timing (upfront or salvage) were related to LC, whereas age, histology, and complete response (CR) to RT were associated with PFS. Patient age and radiation field size impacted OS. RT is an effective and curative local treatment for early-stage FL and MZL at conventional and reduced radiation doses. Conventional-doses seems to be associated with local response improvement, without significant differences in PFS rates. Age, histology, and response to RT may influence the PFS.

Background Truncated tissue factor (tTF) retargeted by NGR-peptides to aminopeptidase N (CD13) in tumor vasculature is effective in experimental tumor therapy. tTF-NGR induces tumor growth inhibition in a variety of human tumor xenografts of different histology. To improve on the therapeutic efficacy we have combined tTF-NGR with radiotherapy. Methods Serum-stimulated human umbilical vein endothelial cells (HUVEC) and human HT1080 sarcoma cells were irradiated in vitro, and upregulated early-apoptotic phosphatidylserine (PS) on the cell surface was measured by standard flow cytometry. Increase of cellular procoagulant function in relation to irradiation and PS cell surface concentration was measured in a tTF-NGR-dependent Factor X activation assay. In vivo experiments with CD-1 athymic mice bearing human HT1080 sarcoma xenotransplants were performed to test the systemic therapeutic effects of tTF-NGR on tumor growth alone or in combination with regional tumor ionizing radiotherapy. Results As shown by flow cytometry with HUVEC and HT1080 sarcoma cells in vitro, irradiation with 4 and 6 Gy in the process of apoptosis induced upregulation of PS presence on the outer surface of both cell types. Proapoptotic HUVEC and HT1080 cells both showed significantly higher procoagulant efficacy on the basis of equimolar concentrations of tTF-NGR as measured by FX activation. This effect can be reverted by masking of PS with Annexin V. HT1080 human sarcoma xenografted tumors showed shrinkage induced by combined regional radiotherapy and systemic tTF-NGR as compared to growth inhibition achieved by either of the treatment modalities alone. Conclusions Irradiation renders tumor and tumor vascular cells procoagulant by PS upregulation on their outer surface and radiotherapy can significantly improve the therapeutic antitumor efficacy of tTF-NGR in the xenograft model used. This synergistic effect will influence design of future clinical combination studies.

Long-term impact of stage-adapted field reduction in a large cohort of gastric marginal zone lymphoma (gMZL) patients treated conservatively with curative radiation therapy (RT).

PURPOSE:Long-term impact of stage-adapted field reduction in a large cohort of gastric marginal zone lymphoma (gMZL) patients treated conservatively with curative radiation therapy (RT).PATIENTS AND METHODS:Prospective analysis of paper records of 290 patients with stage IE-IIE gMZL, treated in 78 radiotherapeutic institutions in Germany from 1992-2013. Stage-adapted radiation fields decreased from extended field (EF) to involved field (IF) over the course of three consecutive prospective trials of the German Study Group on Gastrointestinal Lymphoma (DSGL). Treatment results were compared between the three cohorts.RESULTS:Overall collective with median age of 60 years, slight male predominance (m: fâ= 1.1: 1) and ratio of disease stage I: stage IIâ= 2.1: 1. Median follow-up 6.4 years in total: 13.0 years in the first gastrointestinal study (GIT 1992), 8.2 years in the second (GIT 1996) and 4.7 years in the third study (DSGL 01/2003). Stage-adapted radiation field decrease together with further technological development led to reduced relative frequencies of acute/chronic adverse effects and until now was accompanied by lower disease recurrence. The third study design with smallest field size (IF in stage I, locoregional EF in stage II) achieved the best survival outcome at the 5 year follow-up (overall survival 92.7%, event-free survival 89.5% and lymphoma-specific survival 100.0%). Disease relapse observed in 10 patients. Cumulative incidence of disease-specific death was 1.7% of the followed patients. Primary disease stage associated with lymphoma-specific survival.CONCLUSION:Stage-adapted reduction towards IF in gMZL …

Adjuvant therapy of local soft tissue sarcomas (STS) after wide surgical excision still is a topic under controversial scientific debate. In this single center report we have offered an adjuvant "sandwich" therapy protocol consisting of 4 cycles of doxorubicin (75 mg/m2 i.v. over 1 h on day 1) followed by ifosfamide (5 g/m2 i.v. over 24 h starting on day 1) and local radiotherapy scheduled between chemotherapy cycles 2 and 3 to 104 consecutive patients after wide surgical excision (R0) of histologically proven high-grade STS. After a mean follow-up of 39 months (range 5-194 months) relapse free survival (RFS) at 2 and 5 years was 68.1% (95% CI, 58.5-77.7%) and 61.2% (95% CI, 50.4-71.6%). When analyzing the 82 STS cases of the extremities only 2- and 5-year RFS was 74.0% (95% CI, 64.0-84.0%) and 65.3% (95% CI, 53.7-76.9%). By intent-to-treat analysis, the overall survival (OS) at 2 years was 87.3% (95% CI, 80.5-94.1%) and 75.6% (95% CI, 65.2-86.0%) at 5 years, while OS for STS of the extremities only cohort was 90.5% (95% CI, 83.7-97.3%) and 79.0% (95% CI, 68.4-89.6%), respectively. Tolerability of the treatment was good. This analysis demonstrates the feasibility of adjuvant chemoradiotherapy and reflects the results of the long lasting intensive multidisciplinary team approach at our "high-volume" sarcoma center. The long-term survival in our patients is among the highest reported and the low local and distant recurrence rate in high-risk STS is at least comparable to the published data.

Background and purpose: This study presents the evaluation of acute and late toxicities of the lung in children and adolescents after irradiation in terms of dose-volume effects. Materials and methods: Irradiated children and adolescents in Germany have prospectively been documented since 2001 in the "Registry for the Evaluation of Side-Effects after Radiotherapy in Childhood and Adolescence (RiSK)"; in Sweden since 2008 in the RADTOX registry. Results: Up to April 2012, 1,392 children were recruited from RiSK, and up to June 2013, 485 from the RADTOX-registry. Of these patients, 295 were irradiated to the lung. Information about acute toxicity was available for 228 patients. 179 patients have been documented concerning late toxicity (>= grade 1: n = 28). The acute toxicity rate was noticeably higher in children irradiated with 5-20 Gy (p < 0.05). In the univariate analysis, a shorter time until late toxicity was noticeably associated with irradiation with 5-15 Gy (p < 0.05). Conclusion: Acute and late toxicities appear to be correlated with higher irradiation volumes and low doses. Our data indicate that similar to the situation in adult patients, V5, V10, V15 and V20 should be kept as low as possible (e.g., at least V5 < 50%, V10 and V15 < 35% and V20 < 30%) in children and adolescents to lower the risk of toxicity. (C) 2017 Elsevier B.V. All rights reserved.

PURPOSE:In the context of oncologic therapy for children, radiation therapy is frequently indicated. This study identified the frequency of and reasons for the development of high-grade acute toxicity and possible sequelae. MATERIALS AND METHODS:Irradiated children have been prospectively documented since 2001 in the Registry for the Evaluation of Side Effects After Radiation in Childhood and Adolescence (RiSK) database in Germany and since 2008 in the registry for radiation therapy toxicity (RADTOX) in Sweden. Data were collected using standardized, published forms. Toxicity classification was based on Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS:As of June 2013, 1500 children have been recruited into the RiSK database and 485 into the RADTOX registry leading to an analysis population of 1359 patients (age range 0-18). A total of 18.9% (n=257) of all investigated patients developed high-grade acute toxicity (grades 3/4). High-grade toxicity of the bone marrow was documented for 63.8% (n=201) of those patients, oral mucositis for 7.6% (n=24), and dermatitis for 7.6% (n=24). Patients with high-grade acute toxicity received concomitant chemotherapy more frequently (56%) than patients with no or lower acute toxicity (31.5%). In multivariate analyses, concomitant chemotherapy, diagnosis of Ewing sarcoma, and total radiation dose showed a statistically noticeable effect (P≤.05) on acute toxicity, whereas age, concomitant chemotherapy, Hodgkin lymphoma, Ewing sarcoma, total radiation dose, and acute toxicity influenced the time until maximal late toxicity. CONCLUSIONS:Generally, high-grade acute toxicity after irradiation in children and adolescence occurs in a moderate proportion of patients (18.9%). As anticipated, the probability of acute toxicity appeared to depend on the prescribed dose as well as concomitant chemotherapy. The occurrence of chronic toxicity correlates with the prior acute toxicity grade. Age seems to influence the time until maximal late toxicity but not the development of acute toxicity.

BackgroundThe registry for the evaluation of side effects after radiotherapy in childhood and adolescence (RiSK) was established to prospectively characterize radiation-associated side effects. The purpose of this analysis was to characterize side effects after radiotherapy to the head and neck in children and adolescents.MethodsRadiation doses have been collected across Germany since 2001. Acute and late side effects were characterized.ResultsUntil January 2010, 133 patients (median age, 12.7 years) were recruited who had received radiotherapy to the salivary glands. Toxicity evaluation was available for 114 patients (median follow-up, 2.9 years). Acute and late toxicity significantly depended on the maximum radiation dose to the salivary glands. An increase of the mean value of maximum dose of 1 Gray (Gy) to the submandibular glands resulted in an odds ratio of 1.04 (range, 1.00-1.08; p=.039) for acute toxicities of the salivary glands and 1.08 (range, 1.03-1.13; p=.001) for acute mucosal toxicities.ConclusionThese data can be used for an individual risk assessment in pediatric head and neck radiotherapy. (c) 2014 Wiley Periodicals, Inc. Head Neck37: 1137-1141, 2015

Curative therapies for Ewing sarcoma have been developed within cooperative groups. Consecutive clinical trials have systematically assessed the impact and timing of local therapy and the activity of cytotoxic drugs and their combinations. They have led to an increase of long-term disease-free survival to around 70% in patients with localized disease. Translational research in ES remains an area in which interdisciplinary and international cooperation is essential for future progress. This article reviews current state-of-the art therapy, with a focus on trials performed in Europe, and summarizes novel strategies to further advance both the cure rates and quality of survival.

Purpose: Recent trials with low-dose total skin electron beam (TSEB) therapy demonstrated encouraging results for treating primary cutaneous T-cell lymphoma (PCTCL). In this study, we assessed the feasibility of different radiation doses and estimated survival rates of different pathologic entities and stages.Methods and Materials: We retrospectively identified 45 patients with PCTCL undergoing TSEB therapy between 2000 and 2015. Clinical characteristics, treatment outcomes, and toxicity were assessed.Results: A total of 49 courses of TSEB therapy were administered to the 45 patients. There were 26 pathologically confirmed cases of mycosis fungoides (MF) lymphoma, 10 cases of Sezary syndrome (SS), and 9 non-MF/SS PCTCL patients. In the MF patients, the overall response rate (ORR) was 92% (50% complete remission [CR]), 70% ORR in SS patients (50% CR), and 89% ORR in non-MF/SS patients (78% CR). The ORR for MF/SS patients treated with conventional dose (30-36 Gy) regimens was 92% (63% CR) and 75% (25% CR) for low-dose (<30-Gy) regimens (P=.09). In MF patients, the overall survival (OS) was 77 months with conventional dose regimens versus 14 months with low-dose regimens (P=.553). In SS patients, the median OS was 48 versus 16 months (P=.219), respectively. Median event-free survival (EFS) for MF in conventional dose patients versus low-dose patients was 15 versus 8 months, respectively (P=.264) and 19 versus 3 months for SS patients (P=.457). Low-dose regimens had shorter treatment time (P=.009) and lower grade 2 adverse events (P=.043). A second TSEB course was administered in 4 MF patients with 100% ORR. There is a possible prognostic impact of supplemental/boost radiation (P<.001); adjuvant treatment (P<.001) and radiation tolerability (P=.021) were detected.Conclusions: TSEB therapy is an efficacious treatment modality in the treatment of several forms of cutaneous T-cell lymphoma. There is a nonsignificant trend to higher and longer clinical benefit for MF and SS patients receiving conventional dose. Lowdose TSEB regimens are well tolerated and achieve short-term palliation. (C) 2015 Elsevier Inc. All rights reserved.

Bei Anwendung ionisierender Strahlung in der medizinischen Forschung ist in klinischen Studien im Bereich der Radioonkologie in Deutschland eine Genehmigung durch das Bundesamt für Strahlenschutz (BfS) notwendig. Bei der Abgrenzung zwischen „Heilkunde“ und „medizinischer Forschung“ kommt es bei radioonkologischen Studien immer wieder zu widersprüchlichen Einschätzungen. Ziel ist es, eine Handreichung für Antragsteller, im Beantragungsprozess involvierte Personen und Institutionen sowie Ethikkommissionen zu liefern.

Background and purpose Application of ionizing radiation for the purpose of medical research in Germany needs to be approved by the national authority for radiation protection (Bundesamt fur Strahlenschutz, BfS). For studies in the field of radiation oncology, differentiation between use of radiation for "medical care (Heilkunde)" versus "medical research" frequently leads to contradictions. The aim of this article is to provide principle investigators, individuals, and institutions involved in the process, as well as institutional review or ethics committees, with the necessary information for this assessment. Information on the legal frame and the approval procedures are also provided.Methods A workshop was co-organized by the German Society for Radiation Oncology (DEGRO), the Working Party for Radiation Oncology (ARO) of the German Cancer Society (DKG), the German Society for Medical Physics (DGMP), and the German Cancer Consortium (DKTK) in October 2013. This paper summarizes the results of the workshop and the follow-up discussions between the organizers and the BfS.Results Differentiating between "Heilkunde" which does not need to be approved by the BfS and "medical research" is whether the specific application of radiation (beam quality, dose, schedule, target volume, etc.) is a clinically established and recognized procedure. This must be answered by the qualified physician(s) ("fachkundiger Arzt" according to German radiation protection law) in charge of the study and the treatments of the patients within the study, taking into consideration of the best available evidence from clinical studies, guidelines and consensus papers. Among the important parameters for assessment are indication, total dose, and fractionation. Radiation treatments applied outside clinical trials do not require approval by the BfS, even if they are applied within a randomized or nonrandomized clinical trial. The decision-making by the "fachkundigem Arzt" may be supported on request by an opinion given by the DEGRO Expert Committee for clinical trials.Conclusion An important aim for promoting clinical research and patient care in radiation oncology is to further professionalize planning and implementation of clinical trials in this field. Correct assessment, at an early stage, whether a trial needs to be approved by the BfS may reduce unneccesary costs and reduce the time needed for the approval procedure for those trials which need to be assessed by the BfS.

The German Society of Radiation Oncology (DEGRO) initiated a multicenter trial to develop and evaluate adequate modules to assert core procedures in radiotherapy. The aim of this prospective evaluation was to methodical assess the required resources for radiotherapy in pediatric and adolescent patients.

Background: Local failure after radical prostatectomy (RP) is common in patients with cancer extending beyond the capsule. Three prospectively randomized trials demonstrated an advantage for adjuvant radiotherapy (ART) compared with a wait-and-see (WS) policy.Objective: To determine the efficiency of ART after a 10-yr follow-up in the ARO 96-02 study.Design, setting, and participants: After RP, 388 patients with pT3 pN0 prostate cancer (PCa) were randomized to WS or three-dimensional conformal ART with 60 Gy. The present analysis focuses on intent-to-treat patients who achieved an undetectable prostate-specific antigen after RP (ITT2 population)-that is, 159 WS plus 148 ART men.Outcome measurements and statistical analysis: The primary end point of the study was progression-free survival (PFS) (events: biochemical recurrence, clinical recurrence, or death). Outcomes were compared by log-rank test. Cox regression analysis served to identify variables influencing the course of disease.Results and limitations: The median follow-up was 111 mo for ART and 113 mo for WS. At 10 yr, PFS was 56% for ART and 35% for WS (p < 0.0001). In pT3b and R1 patients, the rates for WS even dropped to 28% and 27%, respectively. Of all 307 ITT2 patients, 15 died from PCa, and 28 died for other or unknown reasons. Neither metastasis-free survival nor overall survival was significantly improved by ART. However, the study was underpowered for these end points. The worst late sequelae in the ART cohort were one grade 3 and three grade 2 cases of bladder toxicity and two grade 2 cases of rectum toxicity. No grade 4 events occurred.Conclusions: Compared with WS, ART reduced the risk of (biochemical) progression with a hazard ratio of 0.51 in pT3 PCa. With only one grade 3 case of late toxicity, ART was safe.Patient summary: Precautionary radiotherapy counteracts relapse after surgery for prostate cancer with specific risk factors. (C) 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Objective Developments in radiation oncology in recent years have highlighted the increasing deployment of personnel resources for tasks not directly related to patients. These tasks include patient-related activities such as treatment planning, reviewing files, and administrative duties (e.g., invoicing for services, documentation). The aim of the present study, part of the QUIRO project of the German Society of Radiation Oncology (DEGRO), was to describe, on the basis of valid data, the deployment of personnel resources in radiation oncology centers for "overhead" tasks.Methods Questionnaires were used to analyze the percentages of time needed for various tasks. The target group comprised physicians, medical physics experts (MPE), and medical technical radiology assistants (MTRA). A total of 760 personnel from 65 radio-oncology centers in the German inpatient and outpatient sector participated (32 % physicians, 23 % MPE, and 45 % MTRA).Results High percentages of overhead tasks during working time were measured for each of the three personnel groups considered (physicians, MPE, and MTRA). Patient-related efficiency, i.e., the percentage of working time associated directly or indirectly with the patient, was highest among MTRA and lowest among MPE. Particular features could be seen in the activity profiles of personnel in university clinics. Duties in the areas of research and teaching resulted in a greater percentage of overhead tasks for physicians and MPE. Irrespective of function (physician, MPE, or MTRA), a managerial role resulted in lower patient-related efficiency, as well as a narrower time budget for direct patient care compared with non-managerial employees.Conclusion Using the data gathered, it was possible to systematically investigate the time required for overhead tasks in radio-oncological centers. Overall, relatively high time requirements for a variety of overhead tasks were measured. These time requirements, generated for example by administrative duties or research and teaching, are currently not taken into adequate consideration in terms of remuneration or personnel capacity planning.

The aim of this study was to evaluate acute and late radiotherapy-associated hepatotoxicity in consideration of dose–volume effects and liver function in childhood and adolescence.