Evaluation of treatment-associated eye toxicity after irradiation in childhood and adolescence-results from the Registry of the Evaluation of Side Effects after Radiotherapy in Childhood and Adolescence (RiSK).

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.

Renaissance of Radiotherapy in Intestinal Lymphoma? 10-Year Efficacy and Tolerance in Multimodal Treatment of 134 Patients: Follow-up of Two German Multicenter Consecutive Prospective Phase II Trials.

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.

Radiotherapy of extranodal low-grade follicular and marginal zone lymphomas: long-term follow-up of 159 patients.

OBJECTIVE: 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. MATERIALS AND METHODS: The medical records of 159 patients with 181 histologically confirmed ENLG-NHL lesions treated at our institution were reviewed retrospectively. RESULTS: 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. CONCLUSION: 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.

Favorable radiation field decrease in gastric marginal zone lymphoma : Experience of the German Study Group on Gastrointestinal Lymphoma (DSGL).

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:f = 1.1:1) and ratio of disease stage I:stage II = 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 5­year 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 resulted in favorable adverse effects, local control and survival rates. These results support further decreases in modern RT of gMZL.

Evaluation of the time required for overhead tasks performed by physicians, medical physicists, and technicians in radiation oncology institutions: the DEGRO-QUIRO study.

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.

[Approval procedures for clinical trials in the field of radiation oncology]. / Genehmigungsverfahren klinischer Studien im Bereich der Radioonkologie.

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 für 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 unnecessary costs and reduce the time needed for the approval procedure for those trials which need to be assessed by the BfS.

Hepatotoxicity after liver irradiation in children and adolescents : results from the RiSK.

AIM: 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. PATIENTS AND METHODS: Since 2001, irradiated children and adolescents in Germany have been prospectively documented in the "Register of Treatment-Associated Late Effects After Radiotherapy of Malignant Diseases in Childhood and Adolescence (RiSK)" using standardized forms. Toxicity was graded according to the Radiation Therapy Oncology Group (RTOG) criteria. RESULTS: Until April 2012, 1,392 children and adolescents from 62 radiotherapy centers were recruited. In all, 216 patients underwent irradiation of the liver (median age 9 years, range 1-18 years, 70 patients with total-body irradiation, TBI). For 75 % of patients without TBI, information on acute toxicity of the liver was available: 24 patients had acute toxicity of grade 1-4 (grade 1, 2, and 4, in 20, 3, and 1 patient, respectively), including five patients receiving simultaneous hepatotoxic chemotherapy. Information on late toxicity was documented in 465 forms from 216 patients, with a median follow-up of 2 years. A maximum grade of toxicity of ≥ 0 occurred in 18 patients over time (with grade 1, 2, and 3 toxicity occurring in 15, 2, and 1 patient, respectively), including three patients (17 %) with TBI. One of them received simultaneous hepatotoxic chemotherapy. In multivariable analysis, volume-dose correlations showed no statistically noticeable effect on acute or chronic toxicity. CONCLUSION: Only low hepatotoxicity developed in children after irradiation of various abdominal and thoracic tumors. Due to the low radiation doses to the liver (median liver dose = 5 Gy) and the low toxicities that were consecutively observed, dose-volume curves for liver toxicity could not be established. These findings reflect the cautious attitude of radiation oncologists in terms of attributable liver doses in the treatment of the investigated tumor entities. It offers the option of increasing these conservative doses if tumor control is necessary.

Evaluation of time, attendance of medical staff and resources for radiotherapy in pediatric and adolescent patients. The DEGRO-QUIRO trial.

BACKGROUND: 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. MATERIAL AND METHODS: At three radiotherapy centers of excellence (University Hospitals of Heidelberg and Münster, the Medical School of Hannover), the manpower and time required for radiotherapy in pediatric and adolescent patients was prospectively documented consistently over a 2-year period. The data were collected using specifically developed standard forms and were evaluated using specific process analysis tools. RESULTS: A total number of 1914 data sets were documented and carefully analyzed. The personnel time requirements for all occupational groups were calculated as total time needed for a specific procedure and mean time per person. Regarding radiotherapy in general anesthesia, the required manpower was higher. The personnel time requirements in these cases were also longer, mainly due to longer room occupancy. Overall, the required resources were remarkably similar between the three different departments and may, therefore, be considered as representative. CONCLUSION: For the first time, the personnel time requirements of a radiotherapy department for the maintenance, protection, and optimization of operational readiness for radiotherapy in pediatric and adolescent patients with and without general anesthesia were determined methodically.

Retrospective, monocentric analysis of late effects after Total Body Irradiation (TBI) in adults.

PURPOSE: Total body irradiation (TBI) is a standard treatment modality within the multidisciplinary approach for allogeneous stem cell or bone marrow transplantation. However, surviving patients are at risk for developing a variety of late sequelae. This analysis aimed to retrospectively characterize late effects after TBI in adults treated in a single center. PATIENTS AND METHODS: Patients ≥ 18 years treated with fractionated TBI (4-12 Gy) between 1996 and 2008 were included in this study. Treatment data were collected retrospectively from the treating departments. Late effects were evaluated using the clinic charts and/or were obtained from the general practitioners using a standardized questionnaire. Analyses were performed by calculation of the cumulative incidences using the Kaplan-Meier method and the log rank test. RESULTS: A total of 308 patients ≥ 18 years were treated including a TBI of whom 78 patients were excluded from further analysis due to death within less than 1 year after TBI. Patients suffered from leukemia in most cases. Late toxicity follow-up was available in 120 patients (mean age 46.1 years; range, 18-70 years) after a mean follow-up of 23 months (range, 12-96 months). The cumulative incidences (CI) at 3 years were 28% for pulmonary event, 8% for pulmonary toxicity, 25% for kidney toxicity, 8% for cataract, 17% for bone toxicity, and 10% for secondary malignancy. The CI of bone toxicity was higher in female than in male patients (p = 0.019). CONCLUSION: Late effects after TBI in the context of allogeneous stem cell or bone marrow transplantation can frequently be observed. Regular follow-up examinations are advised for the early registration and treatment of adverse effects.

[The significance of radiation therapy for symptomatic vertebral hemangiomas (SVH)]. / Der Stellenwert der Strahlentherapie bei symptomatischen Wirbelkörperhämangiomen (sWKH).

PURPOSE: To evaluate the efficacy of radiation therapy (RT) for symptomatic vertebral hemangioma (SVH). MATERIAL AND METHODS: Based on the Registry for Rare Benign Disorders (RRBD) of the German Cooperative Group on Radiation Therapy for Benign Diseases (GCG-BD), the clinical information, treatment plans and outcome data from seven cooperating German RT institutions were analyzed retrospectively. RESULTS: Over a period of 39 years (1969-2008), a total of 84 patients with 96 symptomatic lesions underwent RT. The predominant indication was pain in 97.6%, and, in addition, 28.6% of patients had neurological deficits. The median total dose was 34 Gy (4.5-45 Gy), and the median single dose 2.0 Gy (0.5-3.0 Gy). After a median follow-up of 68 months (6-422 months), complete symptom relief (CR) occurred in 61.9% of patients, 28.6% had partial relief, and 9.5% had no relief (NR). The overall response rate (CR + PR) was 90.5%. In 26.2% of patients, radiologic signs of remineralization were noted. After a median follow-up of 70 months (8-124 months), symptom progression occurred in eight patients (9.5%). Therefore, the long-term rate of local control was 80.9%. Multivariate statistical analysis revealed a significantly higher rate of symptom relief and local control for total doses > or = 34 Gy. Side effects > RTOG/EORTC grade 2 were not observed. CONCLUSION: RT is a safe and effective for treatment of SVH. Total doses of at least 34 Gy are recommended to achieve optimal treatment response.

Radiation synergizes with antitumor activity of CD13-targeted tissue factor in a HT1080 xenograft model of human soft tissue sarcoma.

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.

Multicentric investigation of ionising radiation-induced cell death as a predictive parameter of individual radiosensitivity.

In the present study, the predictive value of ionising radiation (IR)-induced cell death was tested in peripheral blood lymphocytes (PBLs) and their corresponding Epstein-Barr virus-transformed lymphoblastoid cell lines (LCLs) in an interlaboratory comparison. PBLs and their corresponding LCLs were derived from 15 tumour patients, that were considered clinically radiosensitive based on acute side-effects, and matched controls. Upon coding of the samples, radiosensitivity of the matched pairs was analysed in parallel in three different laboratories by assessing radiation-induced apoptotic and necrotic cell death using annexin V. All participating laboratories detected a dose-dependent increase of apoptosis and necrosis in the individual samples, to a very similar extent. However, comparing the mean values of apoptotic and necrotic levels derived from PBLs of the radiosensitive cohort with the mean values of the control cohort did not reveal a significant difference. Furthermore, within 15 matched pairs, no sample was unambiguously and independently identified by all three participating laboratories to demonstrate in vitro hypersensitivity that matched the clinical hypersensitivity. As has been reported previously, apoptotic and necrotic cell death is barely detectable in immortalised LCL derivatives using low doses of IR. Concomitantly, the differences in apoptosis or necrosis levels found in primary cells of different individuals were not observed in the corresponding LCL derivatives. All participating laboratories concordantly reasoned that, with the methods applied here, IR-induced cell death in PBLs is unsuitable to unequivocally predict the individual clinical radiosensitivity of cancer patients. Furthermore, LCLs do not reflect the physiological properties of the corresponding primary blood lymphocytes with regard to IR-induced cell death. Their value to predict clinical radiosensitivity is thus highly questionable.

Long-term results of radiotherapy in primary carcinoma of the vagina.

BACKGROUND: The long-term results of radiotherapy in primary carcinoma of the vagina are not well defined. PATIENTS AND METHODS: The treatment results of 41 patients with primary malignancies of the vagina were analyzed. The mean follow-up period was 77.3 months (2.3-404 months). The predominant histology was squamous cell carcinoma, FIGO stages I: n = 7 (17.1%), II: n = 13 (31.7%), III: n = 13 (31.7%), and IVa: n = 8 (19.5%). Radiotherapy was the primary treatment for all patients. None of the patients had undergone prior surgery for vaginal carcinoma. The majority of patients received pelvic irradiation, including treatment of the inguinal lymphatics (median dose: 50 Gy). 26 patients received additional intravaginal brachytherapy. RESULTS: Overall, 21 patients (51.2%) achieved complete remission, 17 patients (41.5%) had partial responses, and three patients (7.3%) had no change or progressive disease. The total median survival of the analyzed patients was 41.3 months. The 1-year survival probability was 85.4%, the 5-year survival probability 40.6%, and the 10-year survival probability 27.2%. Univariate analysis revealed a survival advantage for earlier tumor stages (FIGO I and II) compared to advanced stages (FIGO III and IV), with a median survival of 58.1 months compared to 26.8 months. Treatment side effects were tolerable and easily managed. CONCLUSION: Definite radiotherapy is the treatment of choice for primary carcinomas of the vagina. Considering that primary malignancies of the vagina are typically diseases of the elderly, it should be noted that radiotherapy is especially well tolerated in this population.

Impact of (18)F-FDG-PET/CT on staging and irradiation of patients with locally advanced rectal cancer.

PURPOSE: To investigate the impact of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) on planning of neoadjuvant radiotherapy for locally advanced rectal cancer (LARC) patients. PATIENTS AND METHODS: From January 2003 to December 2007, a total of 36 patients with LARC underwent a retroprospective PET/CT study for radiotherapy-planning purposes. Gross tumor volume (GTV), clinical target volume (CTV) and planning target volume (PTV) were defined in a retrospective analysis by a blinded reader. The hypothetical boost volume was defined primarily on CT alone, and afterwards on the fused PET/CT dataset. The CT- and PET/CT-based GTVs were quantitatively compared and percentage of overlap (OV%) was calculated and analyzed. The impact of PET/CT on radiation treatment planning and overall patient management was evaluated. RESULTS: PET/CT-GTVs were smaller than CT-GTVs (p < 0.05). PET/CT imaging resulted in a change of overall management for three patients (8 %). In 16 of 35 patients (46 %), PET/CT resulted in a need for modification of the usual target volumes (CT-PTV) because of detection of a geographic miss. CONCLUSION: FDG-PET/CT had significant impact on radiotherapy planning and overall treatment of patients with LARC.

Clinical outcomes of adjuvant external-beam radiotherapy for differentiated thyroid cancer - results after 874 patient-years of follow-up in the MSDS-trial.

AIM: Evaluate the clinical benefit of external beam radiotherapy (RTx) for locally invasive thyroid carcinoma with follicular cell differentiation (DTC). PATIENTS, METHODS: The Multicentre Study on Differentiated Thyroid Cancer (MSDS) was planned as a prospective multicenter trial on the benefit of adjuvant RTx in locally invasive DTC (pT4; UICC 1997) with or without lymph node metastases and no known distant metastases. All patients were treated with thyroidectomy, 131I-therapy, and TSH-suppression and were randomized to receive additional RTx or not. In 4/2003 the trial became a prospective cohort study after only 45 of then 311 patients had consented to randomization. 351 of 422 patients met the trial's inclusion criteria. Age was 48 +/- 12 years (mean +/- SD). 25% were men. Tumours were papillary in 90% and follicular in 10%. Of 47 patients randomized or allocated to RTx, 26 actually received RTx. RESULTS: Mean follow-up was 930 days. In an actual treatment analysis, 96% (25/26) of the RTx-patients reached complete remission (CR) vs. 86% in the non-RTx patients. Recurrences occurred in 0 vs. 3 % of patients: 6 reoperated for regional lymph node metastases, 1 tracheal invasion treated with tracheoplasty, 1 local invasion necessitating laryngectomy, 2 distant metastases (1 lung, 1 lung + bone). Serious chronic RTx toxicity occurred in 1/26 patients. CONCLUSION: The MSDS trial showed low mortality and recurrence rates and a weak benefit of RTx in terms of local control that did however not reach statistical significance. Routine RTx in locally invasive DTC can no longer be recommended.

Quality control of involved field radiotherapy in patients with early-favorable (HD10) and early-unfavorable (HD11) Hodgkin's lymphoma: an analysis of the German Hodgkin Study Group.

PURPOSE: The German Hodgkin Study Group (GHSG) set up a radiotherapy (RT) reference center within the Department of Radiation Oncology at the University of Cologne to undertake quality assurance of the group's clinical studies. In the HD10 trial (early-favorable stages) and HD11 trial (early-unfavorable stages) all patients received involved field (IF)-RT (30 Gy vs. 20 Gy) within a combined-modality approach. For these patients a central prospective review of all diagnostic imaging was performed by expert radiation oncologists to control disease extension and to define IF treatment volume. METHODS AND MATERIALS: On the basis of simulation films, verification films, and radiotherapy case report form (CRF) an expert panel evaluated retrospectively the adequacy of irradiated IF treatment portals according to the RT prescription, applied radiation doses, treatment time, and technical parameters. RESULTS: Between 1999 and 2006 a total of 825 of 1370 randomized patients of the HD10 trial (60%) and 954 of 1422 patients of the HD11 trial (67%) were evaluated by the panel. Radiotherapy was rated as suboptimal in 47% of all reviewed cases. Although the participating RT centers received a precise RT prescription, most difficulties occurred in the adequate coverage of the IF (40%), followed by technical faults (12%). Deviations from the prescribed single daily dose (1.8-2 Gy), weekly dose, and total reference dose were rare (1%). CONCLUSIONS: As a consequence of these findings, radiation oncologists were trained on the definition of IF-RT at GHSG meetings and at the annual meetings of the German Society for Therapeutic Radiation Oncology. Possible correlations between RT quality and relapse rate will be investigated.

Perioperative high-dose rate brachytherapy using a bendy applicator (flab): treatment results of 74 patients.

BACKGROUND: Radiotherapy plays a pivotal role in tumor treatment. Brachytherapy as an additional radiation technique allows local dose increments in areas at high risk of local failure. PATIENTS AND METHODS: Our past 15-year experience with tissue-equivalent bendy applicator brachytherapy at the University Hospital Münster, Germany was reviewed. A series of 74 consecutive patients who had mainly been treated for sarcomas with perioperative brachytherapy was analyzed with a focus on local relapse-free survival and side-effects. RESULTS: The 5-year local control rate was 73% in primary treatment situations with a significant influence of additional external irradiation, surgical margin depth and tumor entity. Late sequelae of combined modality treatment were observed in 40 patients (54%) and mainly concerned wound healing (n = 18, 24%). CONCLUSION: A high-risk collective, in view of local failure, showed adequate local control rates as well as acceptable late sequelae. Flab brachytherapy is a good treatment option to achieve local radiation dose increments in patients at high risk of local failure.

Adjuvant chemotherapy-Radiotherapy-Chemotherapy sandwich protocol in resectable soft tissue sarcoma: An updated single-center analysis of 104 cases.

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.

Rectum dose reduction and individual treatment plan optimization for high-dose-rate prostate brachytherapy.

PURPOSE: Different doses and techniques used in high-dose-rate (HDR) prostate brachytherapy make it difficult to define universal quality parameters. The aim of this study was to develop individual, objective parameters for the evaluation of an HDR brachytherapy plan for prostate radiation. METHODS: Fifty-three patients who received an HDR brachytherapy boost after external radiation were analyzed in this study. Brachytherapy was performed with a (192)Ir source after ultrasound-guided, transperineal metal needle application followed by removal of the ultrasound probe to reduce organ dose levels at the anterior rectum wall. The rectum and prostate locations as well as the dose at the anterior rectum wall were estimated under the anatomical conditions of HDR prostate brachytherapy. The doses at the organs at risk (rectum and urethra) were analyzed for several parameters, which were compared to values of former patients before the start of treatment. In cases of major deviations, modifications of the treatment plan were performed before starting the treatment. RESULTS: Deflating of the water balloon led to an increase of the space between the anterior rectal wall and the dorsal margin of the prostate (mean, 6mm; 1-10mm). The dose of the introduced "virtual rectum," represented by the ventral surface of the ultrasound probe, in the treatment plan correlated to dose measurements in the rectum. Pretreatment evaluation and comparison of the established individual quality parameters led in two cases to a treatment plan modification. CONCLUSIONS: This method allows a fast and objective individual brachytherapy treatment plan evaluation and improvement.

Lung toxicity after radiation in childhood: Results of the International Project on Prospective Analysis of Radiotoxicity in Childhood and Adolescence.

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 5-20Gy (p < 0.05). In the univariate analysis, a shorter time until late toxicity was noticeably associated with irradiation with 5-15Gy (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.