Development of curative therapies for Ewing sarcomas by interdisciplinary cooperative groups in Europe.

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.

The QUIRO Study (assurance of quality and innovation in radiooncology): methodology, instruments and practices.

PURPOSE: The QUIRO study aimed to establish a secure level of quality and innovation in radiation oncology. Over 6 years, 27 specific surveys were conducted at 24 radiooncological departments. In all, 36 renowned experts from the field of radiation oncology (mostly head physicians and full professors) supported the realization of the study. METHODS: A salient feature of the chosen methodological approach is the "process" as a means of systematizing diversified medical-technical procedures according to standardized criteria. On the one hand, "processes" as a tool of translation are adapted for creating and transforming standards into concrete clinical and medical actions; on the other hand, they provide the basis for standardized instruments and methods to determine the required needs of physicians, staff, and equipment. In the foreground of the collection and measurement of resource requirements were the processes of direct service provision which were subdivided into modules for reasons of clarity and comprehensibility. Overhead tasks (i.e., participation in quality management) were excluded from the main study and examined in a separate survey with appropriate methods. RESULTS: After the exploration of guidelines, tumor- or indication-specific examination and treatment processes were developed in expert workshops. Moreover, those specific modules were defined which characterize these entities and indications in a special degree. Afterwards, these modules were compiled according to their time and resources required in the "reference institution", i.e., in specialized and as competent recognized departments (mostly from the university area), by various suitable survey methods. CONCLUSION: The significance of the QUIRO study and the validity of the results were optimized in a process of constant improvements and comprehensive checks. As a consequence, the QUIRO study yields representative results concerning the resource requirement for specialized, qualitatively and technologically highly sophisticated radiooncologic treatment in Germany.

Pelvic Ewing sarcomas. Three-dimensional conformal vs. intensity-modulated radiotherapy.

PURPOSE: The goal of the present work was to assess the potential advantage of intensity-modulated radiotherapy (IMRT) over three-dimensional conformal radiotherapy (3D-CRT) planning in pelvic Ewing's sarcoma. PATIENTS AND METHODS: A total of 8 patients with Ewing sarcoma of the pelvis undergoing radiotherapy were analyzed. Plans for 3D-CRT and IMRT were calculated for each patient. Dose coverage of the planning target volume (PTV), conformity and homogeneity indices, as well as further parameters were evaluated. RESULTS: The average dose coverage values for PTV were comparable in 3D-CRT and IMRT plans. Both techniques had a PTV coverage of V95 > 98 % in all patients. Whereas the IMRT plans achieved a higher conformity index compared to the 3D-CRT plans (conformity index 0.79 ± 0.12 vs. 0.54 ± 0.19, p = 0.012), the dose distribution across the target volumes was less homogeneous with IMRT planning than with 3D-CRT planning. This difference was statistically significant (homogeneity index 0.11 ± 0.03 vs. 0.07 ± 0.0, p = 0.035). For the bowel, Dmean and D1%, as well as V2 to V60 were reduced in IMRT plans. For the bladder and the rectum, there was no significant difference in Dmean. However, the percentages of volumes receiving at least doses of 30, 40, 45, and 50 Gy (V30 to V50) were lower for the rectum in IMRT plans. The volume of normal tissue receiving at least 2 Gy (V2) was significantly higher in IMRT plans compared with 3D-CRT, whereas at high dose levels (V30) it was significantly lower. CONCLUSION: Compared to 3D-CRT, IMRT showed significantly better results regarding dose conformity (p = 0.012) and bowel sparing at dose levels above 30 Gy (p = 0.012). Thus, dose escalation in the radiotherapy of pelvic Ewing's sarcoma can be more easily achieved using IMRT.

[Technical and methodical developments of radiation oncology from a physician's point of view]. / Die technischen und methodischen Entwicklungen der Radioonkologie aus ärztlicher Sicht.

Technical and methodical developments have changed radiation oncology substantially over the last 40 years. Modern imaging methods, e.g., computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasound (US), have not only improved the detection of tumors but have also become tools for computed treatment planning. Megavoltage irradiation with accelerators using photons and electrons with large and small fields, intensity modulation (IMRT), image-guided radiotherapy (IGRT), stereotactic irradiation and radiosurgery, intraoperative radiotherapy (IORT), and modern remote controlled afterloading brachytherapy have made high precision radiotherapy increasingly possible. Hadron therapy has potential for further developments. Radiation oncology today is an interdisciplinary modality and increasingly considers interactions with new drugs and differentiated surgical methods. There is a strong need for comprehensive evaluation of the new methods and also for translational research in biology of tumors and normal tissue biology as well as in medical physics and techniques.

Evaluation of time, attendance of medical staff, and resources during radiotherapy for breast cancer patients. The DEGRO-QUIRO trial.

BACKGROUND AND PURPOSE: To conform to recommendations regarding the treatment of breast cancer, an estimation of costs and personnel to assure treatment is required. To date no recommendations based on real time measurements are available. The DEGRO (German Society of Radiation Oncology), therefore, initiated a prospective multicenter evaluation of core procedures of radiotherapy. In this analysis, the results regarding human resources and room occupation during the treatment of breast cancer are presented. PATIENTS AND METHODS: Three academic radiation oncology centers (Erlangen, Münster, Mannheim) prospectively documented their workflow and working time for all breast cancer patients from July-October 2008. Subsequently, a statistical analysis was performed. RESULTS: The longest working time of physicians was the definition of the target volume and organs at risk (mean 33 min). Furthermore, physicians needed much time for general tasks, which included conversations. Physicists needed the most time for treatment planning and authorization (64 min), whereas technicians were mostly needed in day-to-day radiotherapy treatment (15 min, 31 min including verification). Despite significant differences in specific steps between centers, overall working times and room occupation were comparable and representative. Special procedures (intraoperative radiotherapy/multicatheter brachytherapy) required considerable amounts of additional working time of physicians and physicists. CONCLUSION: In this prospective analysis, data of human resources and room occupation during treatment of breast cancer are presented for the first time. Each patient consumes about 12 h of human resources for treatment and 3.75 h for general tasks (physicians 4.7 h, physicists 1.8 h, and technicians 9.2 h).

[Seed migration to the vertebral venous plexus after prostate brachytherapy]. / Seedmigration in den vertebralen Venenplexus nach Prostatabrachytherapie.

We report on seed migration to the vertebral venous plexus after low dose rate prostate brachytherapy with (125)I. A 74-year-old man with T1c N0 M0 adenocarcinoma of the prostate with a Gleason score of 6 (3+3) and prostate-specific antigen level of 14.94 ng/ml underwent interstitial prostate brachytherapy. Six weeks after treatment at the follow-up to determine aftercare a migrated seed was detected in the vertebral venous plexus and a second one in the right lung. No tissue damage around the migrated seeds was documented and the patient exhibited no clinical symptoms.

Pediatric radiation oncology in Germany: a study of availability and application.

BACKGROUND: Radiotherapy plays a pivotal role in many multimodal therapy concepts in pediatric oncology. However, the absolute number of irradiated children is estimated to be quite low. The aim of this study was to evaluate the availability and application of pediatric radiation oncology in Germany. METHOD: In summer 2007, a standardized questionnaire was sent to all radiotherapy facilities in Germany. The questions regarded the structure of the departments, the number of irradiated children each year including the distribution of the different diagnoses, the number of curative treatments, inclusion in study trials, and existence of special contact persons for pediatric radiotherapy as well as technical aspects of irradiation of children. RESULTS: Answers to the questionnaires were obtained from 171 departments (77.4%). Of these, 67 (39%) stated to regularly treat children. These departments treated one to nine children in median each year (<5 children/year: 23 departments; >or=20 children: 15 departments). Most of these children suffered from brain tumors, Hodgkin's disease and acute lymphatic leukemia (ALL). Three-dimensional conformal radiotherapy was the most frequent treatment technique; special techniques like intensity-modulated radiotherapy (IMRT) or brachytherapy were rare. CONCLUSIONS: Due to quite low patient numbers treated in most radiotherapy facilities, individual experiences in pediatric radiation oncology can be assumed to be quite limited. As radiotherapy is part of multimodal therapy approaches in pediatric oncology and children treated with radiotherapy are at special risk for potential side effects, pediatric radiation oncology remains a sophisticated area. Therefore radiotherapy reference-institutions implemented by the therapy optimizing protocols are of fundamental importance.

[FDG-PET/CT in oncology. German Guideline]. / FDG-PET/CT in der Onkologie. Leitlinie.

FDG-PET/CT examinations combine metabolic and morphologic imaging within an integrated procedure. Over the past decade PET/CT imaging has gained wide clinical acceptance in the field of oncology. This FDG-PET/CT guideline focuses on indications, data acquisition and processing as well as documentation of FDG-PET/CT examinations in oncologic patients within a clinical and social context specific to Germany. Background information and definitions are followed by examples of clinical and research applications of FDG-PET/CT. Furthermore, protocols for CT scanning (low dose and contrast-enhanced CT) and PET emission imaging are discussed. Documentation and reporting of examinations are specified. Image interpretation criteria and sources of errors are discussed. Quality control for FDG and PET/CT-systems, qualification requirements of personnel as well as legal aspects are presented.

[Register for the evaluation of side effects after radiation in childhood and adolescence--first results]. / Register zur Erfassung von Spätfolgen nach Strahlentherapie im Kindes- und Jugendalter--erste Ergebnisse.

BACKGROUND: Late effects after radiotherapy in childhood and adolescence have mainly been characterized retrospectively with small patient numbers. Therefore the German Group of Pediatric Radiation Oncology (APRO) established the "RegIster for the evaluation of late Side effects after radiation in childhood and adolescence" (RiSK). After a pilot phase starting in 2001 documentation has been performed all over Germany since 2004. This analysis shows the first results of "RiSK". PATIENTS AND METHODS: Radiation parameters including detailed organ doses as well as toxicity evaluations were collected prospectively from centers all over Germany in the study center. Standardized documentation forms were used. Documentation is planned for all children who receive radiotherapy in one of the German pediatric therapy trials. RESULTS: Until December 31st 2006, 696 documentations of radiotherapy and 526 acute as well as 836 late follow-up documentation forms have been collected. Altogether, 41 patients with late grade 3 and 16 patients with late grade 4-side effects were identified. Side effects mainly concerned joints with functional impairment (after combined radiotherapy and surgery), the bowel, skin and subcutis as well as blood parameters under continued chemotherapy. Patients with late side effects of a higher grade were mainly treated for Ewing's or soft tissue sarcomas (n=235 patients), representing 33.8% of all patients in this study. CONCLUSION: Fortunately, up to now only a few late grade 3 or 4 side effects of radiotherapy are shown for almost 700 documented patients. For further results, especially for the characterization of dose-effect-relationships, this study has to be continued with a higher patient number and a longer follow-up.

[Requirements and performance profile of the Paediatric Radiation Oncology Working Group (APRO): evaluation of the present situation and description of future developments]. / Anforderungen und Leistungsprofile der Arbeitsgemeinschaft Pädiatrische Radioonkologie (APRO): Eine Bestandsaufnahme und Darstellung zukünftiger Entwicklungen.

BACKGROUND: Radiation therapy is an integral component in the management of childhood malignancies and undergoes a continuous process of optimization within the prospective trials of the GPOH. At present there are approximately 20 active protocols, some specifying radio-oncological study questions, in which about 500 to 600 children annually are given radiotherapy. MATERIALS/METHODS: The Pediatric Radiation Oncology Working Group (APRO) of the German Society for Radiation Oncology (DEGRO) represents the organizational link between GPOH and DEGRO. Their activities range from phrasing guidelines of radio-oncological therapy, through writing a protocol for a prospective study on radiation-induced late effects (RISK--in co-operation with GPOH, 695 patients registered so far) and organizing meetings for information transfer, to implementing radio-oncology within the prospective studies of the GPOH by establishing study chairs for radio-oncology when radio-oncological questions are a primary focus and/or to function as a reference institution for quality assurance. These activities also include individual case consultations outside the study proper. Twice annually the members of the APRO meet for an update on current knowledge and future directions where a representative of the GPOH is invited to contribute special aspects of pediatric oncology. CONCLUSIONS: In the future, modern technology (intensity modulated radiotherapy, proton therapy, inclusion of imaging in treatment planning) will be part of disease management in pediatric oncology. A working group for modern radiotherapy technology was established to enhance this development. Prospective studies of the GPOH with primary or secondary radio-oncological questions require the implementation of corresponding tasks (documentation, monitoring, etc.) in order to meet future demands on clinical trials and to achieve the aims of the protocol. Consequently adequate financial support is indispensable.

Thyroid function in paediatric and young adult patients after sarcoma therapy: a report from the Late Effects Surveillance System.

OBJECTIVE: The role of chemotherapy in thyroid sequelae after cancer treatment has not been studied systematically, especially in sarcoma patients. The aim of this study was to determine the incidence of post-therapeutic thyroid disorders and their contributing factors in a cohort of paediatric sarcoma patients. DESIGN: Late effects of sarcoma treatment have been collected prospectively within the Late Effects Surveillance System (LESS) in Germany, Austria and Switzerland since 1998. PATIENTS: We studied 340 relapse-free paediatric patients (median age at diagnosis 12.2 [interquartile range (IQR) = 7.3-15.6 years] treated for osteosarcoma, soft tissue sarcoma or Ewing's sarcoma within the COSS-96, CWS-96/CWS-2002P or EICESS-92/EURO-E.W.I.N.G.-99 therapy trials. In addition to polychemotherapy, 127 patients were irradiated (mean cumulative dose 47 +/- 9.7 Gy), including 51 patients with irradiation to the head/neck region. Median follow-up was 24.6 (IQR = 11.9-44.9) months. MEASUREMENTS: We reviewed the results of yearly examinations of serum TSH and fT4 levels and thyroid ultrasound examinations. RESULTS: The incidence of thyroid disorders was 37% (19/51, 95% CI 24-52%) in patients with head/neck irradiation, and 11% (32/289, 95% CI 8-15%) in patients without irradiation to the head/neck. Thyroid disorders were more frequent in patients treated with idarubicin (P = 0.027) and trofosfamide (P = 0.016). We also found a significant association between raised TSH levels and treatment with trofosfamide (P = 0.008) or idarubicin (P = 0.037) (n = 250). CONCLUSIONS: The incidence of thyroid disorders in the head/neck-irradiated group was high. Even without head/neck irradiation, we found an increased proportion of patients with thyroid disorders, possibly as a result of chemotherapy.

Alpha-fetoprotein-positive carcinoma of the pancreas: a case report.

We report on the case of a 19-year-old male with an alpha-fetoprotein (AFP)-producing acinar cell carcinoma of the pancreas. Tumour markers other than AFP were normal. Because of inoperability, a combined radiochemotherapy was initiated with a hyperfractionated dose of 44.8 Gy. Initially, the tumour showed a good response to irradiation and 5-fluorouracil (5-FU) application, and therapy showed sufficient local control. After combined radio-chemotherapy, AFP levels declined from about 3000 ng/ml (reference area: 0-7 ng/ml) to 18 ng/ml, but increased when widespread metastasis appeared. The patient died 18 months after the initial therapy due to general tumour progression. Originally, AFP was thought to be specific to hepatocellular carcinoma and germ cell tumours. Rarely has it been reported in other malignancies. Rare cases of acinar cell carcinomas of the pancreas were found to express AFP. Our patient is the youngest reported in the literature to date. When present, AFP expression is useful for diagnosis and as a marker for monitoring therapeutic response and recurrence of the disease.

[Plantar fasciitis and radiotherapy. Clinical and radiobiological treatment results]. / Plantare Fasziitis und Strahlentherapie Klinische und strahlenbiologische Ergebnisse der Behandlung.

Patients with plantar fasciitis and pain refractory to conventional therapy are treated with low-dose radiotherapy (RT), but no conclusive evidence-based and radiobiological studies had been performed. In 2001 the German Cooperative Group on Radiotherapy for Benign Diseases (GCG-BD) carried out a study by mailing a standardized questionnaire. A total of 136 institutions treated 3621 patients/year with chronic or refractory pain. The median total dose was 6 Gy (median single dose: 1 Gy); 76 institutions reported data of their clinical evaluation of a total of 7947 patients. Pain relief lasting for at least 3 months was reported in 70% and persistent pain relief in 65%. There were no acute or chronic radiogenic side effects observed. The radiobiological studies showed a significant increase of granulocyte function at 1.5 Gy and a significant decrease at 3.5 and 4.0 Gy. These results may provide a possible explanation for a local anti-inflammatory effect of low-dose RT. RT may be an excellent alternative for patients with contraindications to long-term treatment with steroids or NSAID.

Heterogeneity of radiation induced apoptosis in Ewing Tumor cell lines characterized on a single cell level.

The objective of this study was to investigate heterogeneity of radiation induced apoptosis on a single cell level. Two Ewing tumor cell lines were characterized in vitro before and 24 and 72 h after radiation with 5 Gy by multiparametric flow cytometry. Annexin V, 7-AAD and fluorescence conjugated antibodies that were directed against HLA-ABC, CD11a and CD62L were used. Based on these markers radiation induced apoptosis was quantified, multiple apoptotic subpopulations were identified and a characteristic individual apoptotic profile was characterized. The characterization of HLA-ABC, CD11a and CD62L was informative to detect subpopulations of apoptotic cells. The observed heterogeneity and the identification of multiple apoptotic subpopulations reflect the complexity and diversity of biology of radiation induced cell death. This might be an indication for co-existing apoptotic pathways or it might represent sequential steps of the apoptotic cascade.

Guidelines on radioiodine therapy for differentiated thyroid carcinoma: impact on clinical practice.

AIM: For the examination of the impact on clinical practice of the guidelines for differentiated thyroid carcinoma (DTC), treatment data from the ongoing Multicenter Study Differentiated Thyroid Carcinoma (MSDS) were analyzed. PATIENTS, METHODS: Patients were randomized to adjuvant external beam radiotherapy (RTx) or no RTx in addition to standard therapy in TNM stages pT4 pN0/1/x M0/x (UICC, 5th ed. 1997). All patients were to receive the same treatment regimen consisting of thyroidectomy, ablative radioiodine therapy (RIT), and a diagnostic 131I whole-body scintigraphy (WBS) 3-4 months after RIT. RESULTS: Of 339 eligible patients enrolled between January 2000 and March 2004, 273 could be analyzed. Guideline recommendations by the German Society for Nuclear Medicine from 1999 and 1992 were complied with within 28% and 82% with regard to the interval between surgery and RIT (4 vs. 4-6 weeks), in 33% and 84% with regard to 131I activity for RIT (1-3 vs. 1-4 GBq; +/- 10%), and in 16% and 60% with regard to 131I activity for WBS (100-300 vs. 100-400 MBq; +/- 10%). CONCLUSIONS: The 1999 guideline revision appears to have had little impact on clinical practice. Further follow-up will reveal if guideline compliance had an effect on outcomes.

[PET/CT in radiotherapy]. / PET-CT in der Strahlentherapie.

Combining positron emission tomography (PET) and X-ray computed tomography (CT) with simultaneous acquisition may improve diagnostic accuracy in oncology. Moreover this combination holds considerable promise in radiotherapy. Metabolic information may be used in decision making in radiotherapy and in planning target volumes. Furthermore early evaluation of treatment efficacy becomes possible. New tracers for the assessment of tumour hypoxia or apoptosis in clinical routine are currently being developed. These tracers may yield high relevance in radiotherapy. Hybrid scanners facilitate patient handling and shorten the duration of acquisition. Furthermore fusion accuracy is optimal. Prospective studies have to be conducted to show that the new technology improves patient care in terms of efficiency and quality.

Late urologic effects after adjuvant irradiation in stage I endometrial carcinoma.

OBJECTIVES: To evaluate the incidence and type of incontinence after external beam radiotherapy (RT) and brachytherapy. Distinct late effects on the urinary bladder can occur and are frequently mild after adjuvant RT for Stage I endometrial carcinoma. Not all side effects that impair quality of life (eg, urinary incontinence) are classified in the commonly used grading system. METHODS: Forty-one patients were evaluated for newly occurred urinary incontinence after adjuvant RT. The mean follow-up was 64.8 months, and the mean age was 62.1 years. The validated incontinence score from Gaudenz was used. Additionally, quality-of-life questions were asked. RESULTS: Overall, 22 (53.7%) of 41 patients complained of urinary incontinence. Urge incontinence was classified in 45.5% (10 of 22 patients) and stress urinary incontinence in 54.5% (12 of 22 patients). CONCLUSIONS: The onset of stress urinary incontinence after brachytherapy can be explained by anatomic findings, such as adverse affects to the nerve supply of the rhabdosphincter. According to our results, the exposure to additional external beam RT can cause urge incontinence. Patients and doctors must be aware that urinary incontinence, with an occurrence rate of more than 50%, represents the most common side effect after surgery and RT for Stage I endometrial carcinoma. We conclude that, depending on the type of RT, a stress incontinence rate of 24.4% and an urge incontinence rate of 29.2% is possible.

Treatment of advanced Hodgkin's disease with COPP/ABV/IMEP versus COPP/ABVD and consolidating radiotherapy: final results of the German Hodgkin's Lymphoma Study Group HD6 trial.

BACKGROUND: The purpose of this study was to compare the efficacy of the hybrid chemotherapeutic regimen COPP/ABV/IMEP (cyclophosphamide-vincristine-procarbazine-prednisone-doxorubicin-bleomycin-vinblastine-ifosfamide-methotrexate-etoposide) (CAI) with that of the standard regimen COPP/ABVD (COPP/ABV, dacarbacine) (CA) in the treatment of advanced-stage Hodgkin's disease (HD). PATIENTS AND METHODS: Between January 1988 and January 1993, 588 eligible patients with HD in stages IIIB and IV were randomly assigned to a treatment or control group. The treatment group received four cycles of CAI over a complete cycle duration of 43 days. The control group received four cycles of CA over 57 days. Both groups then received consolidating radiotherapy. RESULTS: Five hundred and eighty-four patients were suitable for arm comparison. Patients in each group were similar in age, sex, histological subtype and clinical risk factors. Complete remission rates, overall survival and freedom from treatment failure at 7 years were similar for the two groups: 77% versus 78%, 73% versus 73% and 54% versus 56% for CAI and CA, respectively. Differences in acute chemotherapy-related toxicity were significant, however. Prognostic factor analysis confirmed the relevance of the International Prognostic Index and revealed that stage IVB, low hemoglobin, low lymphocyte count, high age and male gender were associated with a poor prognosis CONCLUSION: The rapidly alternating hybrid CAI did not give superior results when compared with the standard regimen CA in advanced-stage HD.