Frank Bruns

Multicenter, Phase 3 Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology

PURPOSE We assessed whether adjuvant supplementation with selenium improves the selenium status and reduces side effects of patients treated by radiotherapy (RT) for cervical and uterine cancer. METHODS AND MATERIALS Whole-blood selenium concentrations were measured in patients with cervical cancer (n = 11) and uterine cancer (n = 70) after surgical treatment, during RT, at the end of RT, and 6 weeks after RT. Patients with initial selenium concentrations of less than 84μg/L were randomized before RT either to receive 500 μg of selenium (in the form of sodium selenite [selenase, biosyn Arzneimittel GmbH, Fellbach, Germany]) by mouth on the days of RT and 300 μg of selenium on the days without RT or to receive no supplement during RT. The primary endpoint of this multicenter Phase 3 study was to assess the efficiency of selenium supplementation during RT; the secondary endpoint was to decrease radiation-induced diarrhea and other RT-dependent side effects. RESULTS A total of 81 patients were randomized. We enrolled 39 in the selenium group (SG) and 42 in the control group (CG). Selenium levels did not differ between the SG and CG upon study initiation but were significantly higher in the SG at the end of RT. The actuarial incidence of diarrhea of Grade 2 or higher according to Common Toxicity Criteria (version 2) in the SG was 20.5% compared with 44.5% in the CG (p = 0.04). Other blood parameters, Eastern Cooperative Oncology Group performance status, and self-reported quality of life were not different between the groups. CONCLUSIONS Selenium supplementation during RT is effective in improving blood selenium status in selenium-deficient cervical and uterine cancer patients and reduces the number of episodes and severity of RT-induced diarrhea.

Effects of Radiotherapy for Brain Metastases on Quality of Life (QoL)

Background:Prospective data on quality-of-life (QoL) effects of radiotherapy for brain metastases are currently lacking, but would be of great interest to guide therapeutic decisions.Patients and Methods:From 01/2007 to 08/2007, 46 patients with previously untreated brain metastases were recruited at eight centers. QoL was measured at start of treatment (T0) and at 3 months (T3mo). In the pilot study, two combinations of QoL instruments could be used at the discretion of the centers (A: EORTC QLQ-C30 and B: EORTC QLQ-C15-PAL both with brain module BN20, assessment by proxies with A: Palliative Care Outcome Scale, B: self-constructed brain-specific instrument).Results:All patients received whole-brain radiotherapy, four with an additional boost irradiation. At T3mo, 26/46 patients (56.5%) had died. 17/20 survivors (85%) completed the questionnaires. In 3-month survivors, QoL deteriorated in most domains, significant in drowsiness, hair loss and weakness of legs. The scores for headaches and seizures were slightly better after 3 months. Assessment by proxies also suggested worsening of QoL. Initial QoL at T0 was better in those alive than in those deceased at T3mo, significant for physical function and for the symptom scales of fatigue and pain, motor dysfunction, communication deficit and weakness of legs.Conclusion:Practicability and compliance appeared better with the (shorter) version B. This version is now used in the ongoing main phase of the study with additional centers. First results indicate a moderate worsening of QoL during the first 3 months after start of palliative radiotherapy for brain metastases. QoL at initiation of radiotherapy may be prognostic for survival.Hintergrund:Prospektive Daten über die Auswirkung einer palliativen Strahlentherapie auf die Lebensqualität (LQ) von Patienten mit Hirnmetastasen existieren nur wenige, jedoch sind sie von großem Interesse für Therapieentscheidungen.Patienten und Methodik:Von 01/2007 bis 08/2007 wurden an acht Zentren 46 Patienten mit bisher unbehandelten Hirnmetastasen rekrutiert (Tabelle 1). Die LQ vor und 3 Monate nach palliativer Strahlentherapie wurde erhoben. In der Pilotphase konnten die Zentren zwischen zwei Kombinationen von Instrumenten wählen (A: EORTC QLQ-C30 und B: QLQ C15-PAL jeweils mit Hirnmodul BN20, Fremdeinschätzung durch Angehörige mittels A: Palliative Care Outcome Scale, B: eigenen Hirnmoduls).Ergebnisse:Alle Patienten erhielten eine Ganzhirnbestrahlung, vier Patienten zusätzlich eine Boostbestrahlung. 3 Monate nach Therapiebeginn waren 26/46 Patienten (56,5%) verstorben. Die Rücklaufquote der Fragebögen der Überlebenden betrug 17/20 (85%). Für dieses Kollektiv der 3-Monats-Überlebenden zeigte die Selbsteinschätzung eine Verschlechterung in den meisten Bereichen, signifikant für Schläfrigkeit, Alopezie und Beinschwäche. Die Scores für Kopfschmerzen und Krampfleiden waren nach 3 Monaten etwas besser (Abbildung 1). Die Fremdeinschätzungen zeigten ebenfalls eine zunehmende Beeinträchtigung der Patienten nach 3 Monaten (Abbildung 2). Die initiale LQ war bei den 3-Monats-Überlebenden (Abbildung 3a) im Vergleich zu den Verstorbenen besser, signifikant für die körperliche Funktion und für die Symptomskalen Fatigue, Schmerz (Abbildung 3b), motorische Dysfunktion, Kommunikationsdefizit und Beinschwäche (Abbildung 3c).Schlussfolgerung:Die kürzere Fragebogenvariante B schien bezüglich der Praktikabilität und Compliance besser zu sein. Demzufolge wird diese Variante in der aktuell laufenden Hauptphase mit zusätzlichen Zentren verwendet (Abbildung 4). Erste Ergebnisse deuten auf eine mäßige LQ-Verschlechterung bei 3-Monats-Überlebenden hin. Möglicherweise könnte die initiale objektivierte LQ als prädiktiver Faktor herangezogen werden.

Radiotherapy for Symptomatic Vertebral Hemangiomas: Results of a Multicenter Study and Literature Review

PURPOSE The current study analyzes the potential role of radiotherapy (RT) in symptomatic vertebral hemangioma (SVH). METHODS AND MATERIALS Seven cooperating German institutions collected clinical information, treatment plans, and outcome data for all patients with SVH referred for local RT. RESULTS From 1969 to 2008, a total of 84 patients with 96 symptomatic lesions were irradiated for SVH. The primary indication for radiotherapy was pain (97.6%), and 28.6% of patients had additional neurological symptoms. RT was performed at a median total dose of 34 Gy, with a median single dose of 2.0 Gy. After receiving a median follow-up of 68 months, the overall patient response rate was 90.5%. Complete symptom remission occurred in 61.9% of patients, 28.6% of patients had partial pain relief, and 9.5% of patients had no pain relief. In 26.2% of patients, radiological signs of reossification were observed in long-term follow-up but not significantly correlated with pain relief. Most importantly, total doses of >/=34 Gy resulted in significantly greater symptomatic relief and control rate than total doses of <34 Gy. CONCLUSIONS This study consists of the largest database of cases reported so far using RT for SVH. RT is easy, safe, and effective for pain relief treatment for SVH. Total doses of at least 34 Gy give the best symptomatic response.

Prospective evaluation of quality of life effects in patients undergoing palliative radiotherapy for brain metastases

BackgroundRecently published results of quality of life (QoL) studies indicated different outcomes of palliative radiotherapy for brain metastases. This prospective multi-center QoL study of patients with brain metastases was designed to investigate which QoL domains improve or worsen after palliative radiotherapy and which might provide prognostic information.MethodsFrom 01/2007-01/2009, n=151 patients with previously untreated brain metastases were recruited at 14 centers in Germany and Austria. Most patients (82 %) received whole-brain radiotherapy. QoL was measured with the EORTC-QLQ-C15-PAL and brain module BN20 before the start of radiotherapy and after 3 months.ResultsAt 3 months, 88/142 (62 %) survived. Nine patients were not able to be followed up. 62 patients (70.5 % of 3-month survivors) completed the second set of questionnaires. Three months after the start of radiotherapy QoL deteriorated significantly in the areas of global QoL, physical function, fatigue, nausea, pain, appetite loss, hair loss, drowsiness, motor dysfunction, communication deficit and weakness of legs. Although the use of corticosteroid at 3 months could be reduced compared to pre-treatment (63 % vs. 37 %), the score for headaches remained stable. Initial QoL at the start of treatment was better in those alive than in those deceased at 3 months, significantly for physical function, motor dysfunction and the symptom scales fatigue, pain, appetite loss and weakness of legs. In a multivariate model, lower Karnofsky performance score, higher age and higher pain ratings before radiotherapy were prognostic of 3-month survival.ConclusionsModerate deterioration in several QoL domains was predominantly observed three months after start of palliative radiotherapy for brain metastases. Future studies will need to address the individual subjective benefit or burden from such treatment. Baseline QoL scores before palliative radiotherapy for brain metastases may contain prognostic information.

12 years' experience with intraoperative radiotherapy (IORT) of malignant gliomas

Background:Even after surgery and radiotherapy, malignant gliomas still have a poor prognosis. The authors report on their experience with IORT in 71 patients.Patients and Methods:From May 1992 to February 2004, 71 patients with malignant gliomas were treated with IORT. 26 patients suffered from grade III gliomas, 45 patients from glioblastomas (GBM). IORT was carried out using a standard electron tube and 9- to 18-MeV electrons. 52/71 patients who were primarily treated received 20 Gy IORT + 60 Gy postoperative radiotherapy, 19/71 patients with recurrences only received IORT (20–25 Gy).Results:The complication rates were 1.4% for wound infections and 5.6% for hemorrhage. Median disease-specific survival amounted to 14.9 months (gliomas III) and 14.2 months (GBM). The 2-year survival rates amounted to 26.9% (gliomas III) and 6.8% (GBM; p = 0.0296). Total versus subtotal resection had no significant influence on survival (p = 0.0741), nor had age, sex, tumor site, performance status, size, primary versus recurrence, and radiation dose. A comparison to a conventionally treated patient group did not show a significant survival improvement. 3 months after treatment, initial symptoms had improved in 59% (hemiparesis), 50% (aphasia), 50% (hemianopsia), and 60% (convulsions).Conclusion:IORT has been shown to be feasible; perioperative complication rates were not increased. Survival was generally not improved compared to a historical control group. Recurrences achieved the same survival as primary tumors, and GBM also had a slightly increased survival, thus being possible indications for IORT.Hintergrund:Auch nach Resektion und Strahlentherapie haben maligne Gliome nach wie vor eine schlechte Prognose. Die Autoren berichten über ihre Erfahrungen mit der IORT bei 71 Patienten.Patienten und Methodik:Von Mai 1992 bis Februar 2004 wurden 71 Patienten mit malignen Gliomen mit IORT behandelt. 26 Patienten hatten Grad-III-Gliome, 45 Patienten Glioblastome (GBM). Die IORT wurde mittels eines üblichen Elektronentubus und 9- bis 18-MeV-Elektronen durchgeführt. 52/71 Patienten wurden primär mit 20 Gy IORT + 60 Gy postoperativer Radiotherapie behandelt, 19/71 Patienten mit Rezidiven erhielten nur eine IORT (20–25 Gy).Ergebnisse:Die Komplikationsraten betrugen 1,4% für Wundinfektionen und 5,6% für Blutungen. Das mediane krankheitsspezifische Überleben lag bei 14,9 Monaten (Gliome III) und 14,2 Monaten (GBM). Die 2-Jahres-Überlebensraten betrugen 26,9% (Gliome III) und 6,8% (GBM; p = 0,0296). Der Resektionsstatus hatte keinen signifikanten Einfluss (p = 0,0741), ebenso wenig Alter, Geschlecht, Lokalisation, Allgemeinzustand, Größe, Primärtumor versus Rezidiv und Bestrahlungsdosis. Ein Vergleich mit einem konventionell behandelten Patientenkollektiv zeigte keine signifikante Verbesserung des Überlebens. 3 Monate nach Therapie hatten sich die initialen Symptome in 59% (Hemiparese), 50% (Aphasie), 50% (Hemianopsie) und 60% (Krampfanfälle) gebessert.Schlussfolgerung:Die IORT ist gut durchführbar; die perioperative Komplikationsrate war nicht erhöht. Das Überleben konnte im Vergleich zu einer historischen Kontrollgruppe insgesamt nicht verbessert werden. Rezidive erzielten dasselbe Überleben wie Primärtumoren, und auch GBM erreichten ein etwas besseres Überleben; diese beiden Gruppen sind am ehesten mögliche Indikationen für die IORT.

Adjuvant radiotherapy in stage I seminoma: is there a role for further reduction of treatment volume?

An analysis was performed to determine whether a cranial reduction of the portals to the T11/T12 junction instead of the common T10/T11 junction would alter the outcome of patients with stage I seminoma. Of 163 consecutive patients with newly diagnosed testicular seminoma referred to the authors’ institution between April 1992 and April 1999, 80 patients with stage I seminoma were treated with cranially reduced para-aortic treatment fields reaching from the top of T12 to the bottom of L4. Median total dose was 20.0 Gy (range, 19.8–27.2 Gy). Patients were followed-up by the use of CT in regular intervals. After a median follow-up of 7.1 years (range, 4.1–11.1 years), four patients (5%) had relapsed resulting in an actuarial 5-year relapse-free survival of 95%. No patients relapsed within the cranially reduced treatment volume above the top of T12. The cranial reduction of the para-aortic treatment fields resulted in a median reduction of treatment volume of 16% (range, 13–21%). The achieved median reduction in treatment volume of 16% appears to be relevant and is not associated with an increased relapse rate. This approach is recommended in analogy to the surgical approach in NSGCT to further minimize the risk of radiation-related late effects.

Simulator Verification of the Accuracy of Patient Repositioning after Virtual Simulation

Purpose: To evaluate the frequency and amount of displacements after repositioning a patient on the physical simulator following virtual simulation. Material and Methods: After laser marking at the CT scanner and virtual simulation, patients were repositioned on the simulator. The isocenter obtained from the calculated table movements was checked by fluoroscopically measuring the distances to standardized anatomic landmarks and comparing them to the treatment plan. Results: In 86% of patients, displacements were ≤ 0.5 cm. There was no significant difference between the supine and prone position, diagnosis categories or CT reconstruction indices. The use of immobilization devices and cranial versus body stem localization did make a significant difference. Rates of exact repositioning were high in brain and head and neck patients and comparatively low in abdominal tumors and breast cancer. Conclusions: Immobilization devices play an important role for the precision of radiotherapy. Whenever precixe positioning is possible (e. g. with a head mask), virtual simulation alone might be sufficient. Patients with abdominal and breast tumors, were repositioning precision is often suboptimal, might profit from an additional physical simulation.Zielsetzung: Es wurden die Häufigkeit und das Ausmaß von Abweichungen ausgewertet, die bei der Repositionierung eines Patienten nach virtueller Simulation auf dem konventionellen Simulator auftraten. Material und Methodik: Nach der Laseranzeichnung am CT und der virtuellen Simulation wurden die Patienten (n = 308, Tabellen 1 und 2) auf dem Simulator erneut gelagert (dies geschah routinemäßig zur Umsetzung des Bestrahlungsplans). Das aus den berechneten Tischverschiebungen resultierende Isozentrum wurde überprüft, indem am Simulator die Abstände zu standardisierten anatomischen Strukturen gemessen (Tabelle 3) und mit dem Bestrahlungsplan verglichen wurden. Ergebnisse: Bei 86% der Patienten waren die Abweichungen ≤ 0,5 cm (Abbildungen 1a bis 1d). Simulation in Rücken- oder Bauchlage, Diagnosekategorie und CT-Rekonstruktionsindex unterschieden sich nicht signifikant, der Einsatz von Immobilisationshilfen und die Lokalisation am Kopf gegenüber dem Körperstamm jedoch sehr wohl (Abbildung 2). Die Raten exakter Repositionierung waren bei Hirntumor- und HNO-Patienten hoch und bei Patienten mit abdominellen Tumoren und Mammakarzinomen vergleichsweise niedrig. Schlussfolgerungen: Immobilisationshilfen spielen eine bedeutende Rolle für die Präzision der Strahlentherapie. Bei präziser Lagerung (z. B. Maske) kann u. U. eine virtuelle Simulation allein ausreichen. Aufgrund der schlechteren Repositionierbarkeit könnten Patienten mit abdominellen und Mammatumoren aber von einer zusätzlichen konventionellen Simulation profitieren.

Radiotherapy in langerhans cell histiocytosis - a rare indication in a rare disease.

IntroductionLangerhans Cell Histiocytosis (LCH) represents a rare benign disorder, previously designated as “Histiocytosis X”, “Type II Histiocytosis” or “Langerhans Cell Granulomatosis”. Clinical presentation includes osteolysis, ulcerations of skin and soft tissues but also involvement of the CNS is described.Because treatment concepts are not well defined the German Cooperative Group on Radiotherapy for Benign Diseases performed a retrospective analysis.Methods and materialEight closely cooperating centres collected patients’ data of the past 45 years. As study endpoints disease free survival, recurrent disease, death and therapy related side effects were defined.ResultsA total of 80 patients with histologically proven LCH were irradiated within the past 45 years. According to the LCH classification of Greenberger et al. 37 patients had stage Ia, 21 patients stage Ib, 13 patients stage II and 9 patients stage IIIb and the median age was 29 years. The median Follow up was 54 months (range 9–134 months). A total of 39 patients had a surgical intervention and 23 patients a chemotherapy regimen.Radiation treatment was carried out with a median total dose of 15 Gy (range 3–50.4 Gy). The median single fraction was 2 Gy (range 1.8-3 Gy).Overall, 77% patients achieved a complete remission and 12.5% achieved a partial remission. The long-term control rate reached 80%. Within an actuarial overall 5-year survival of 90% no radiogenic side and late effects ≥EORTC/RTOG II° were observed.ConclusionIn the present study a large collective of irradiated patients was analysed. Radiotherapy (RT) is a very effective and safe treatment option and even low RT doses show sufficient local control.

Radiotherapy of splenomegaly

Purpose:Since the 20th century, radiotherapy (RT) has been used for treatment of symptomatic splenomegaly (SM). SM occurs in association with hematologic disorders. The purpose of this analysis was to determine the indication, treatment concepts, and efficiency of RT.Material and Methods: Clinical features, treatment concepts, and outcome data during the past 20 years were analyzed. Endpoints were pain relief, symptomatic and hematological response, and treatment-related side effects.Results:From 1989–2009, a total of 122 patients received 246 RT courses because of symptomatic SM. Overall 31 patients had chronic myelogenous leukemia (CML), 37 had chronic lymphocytic leukemia (CLL), 23 had osteomyelofibrosis (OMF), 17 had polycythemia vera (PV), 5 had acute myelogenous leukemia, 4 had idiopathic thrombocytopenic purpura (ITP), 3 had non-Hodgkin lymphoma (NHL), and 2 had multiple myeloma (MM). Patients were treated with 60Co gamma rays or 5–15MV photons. The fraction size ranged from 10–200 cGy and the total dose per treatment course from 30–1600 cGy. Significant pain relief was achieved for 74.8% of the RT courses given for splenic pain. At least 50% regression was attained for 77% of the RT courses given for SM. 36 patients died within 2 months due to the terminal nature of their disease. Of the RT courses applied for cytopenia, 73.6% achieved a significant improvement of hematological parameters and reduction of transfusion need. Notable hematologic toxicities were reported < EORTC/RTOG II°.Conclusion:The present analysis documents the efficacy of RT. In addition, RT as a palliative treatment option for symptomatic SM should not be forgotten.Einleitung:Seit Beginn des 20. Jahrhunderts hat die Radiotherapie (RT) ihren festen Stellenwert in der Behandlung einer symptomatischen Splenomegalie (SM). Die SM tritt bei hämatologischen Erkrankungen auf. Klinisch stehen Kapselschmerz sowie eine Zytopenie im Vordergrund. Die vorliegende Analyse untersucht Indikation, RT-Konzepte und die Effektivität der RT.Material und Methode:Patientendaten der letzten 20 Jahre wurden hinsichtlich klinischer Angaben, RT-Konzepte und Ergebnisse evaluiert. Endpunkte waren Schmerzfreiheit, hämatologisches Ansprechen nach RT sowie therapieassoziierte Nebenwirkungen.Ergebnisse:Zwischen 1989 und 2009 wurden 122 Patienten (79 Männer und 43 Frauen) mit insgesamt 246 RT-Serien behandelt. Folgende Grunderkrankungen waren Ursache für die Splenomegalie: CML (31), CLL (37), Osteomyelofibrose, (23), Polycyt haemia vera (17), AML (5), idiopathische Thrombozytopenie (4), Non-Hodgkin-Lymphom (3) und Plasmozytom (2) (Tabelle1). Die Behandlung erfolgte am Telekobalttherapiegerät oder am Linearbeschleuniger (5–15 MeV Photonen). Es wurden Einzelreferenzdosen zwischen 0,1–2 Gy und Gesamtreferenzdosen zwischen 3–16 Gy appliziert (Tabelle 2). Bei 74,8% der RT-Serien (74,8%), die aufgrund einer schmerzhaften Splenomegalie durchgeführt wurden, konnte eine Schmerzlinderung erzielt werden. Bei 77% der RT-Serien kam es zu einer Verkleinerung der Milz um bis zu 50% (Abbildung 1). 36 Patienten verstarben weniger als 2 Monaten nach Abschluss der RT im Rahmen der infausten Prognose ihrer Grunderkrankung. Bei 73,6% der RT-Serien kam es zu einer Verbesserung hinsichtlich Thrombozytopenien und die Transfusionsfrequenz nahm ab (Tabelle 3). Es wurden lediglich hämatologische Toxizitäten < II° (EORTC/RTOG) beobachtet.Schlussfolgerung:Die vorliegende Analyse belegt die hohe Effektivität der RT bei geringem Nebenwirkungsspektrum. Die RT der symptomatischen Splenomegalie sollte als wirksame palliative Option nicht in Vergessenheit geraten.

Improved Regeneration of Autologous Transplanted Lymph Node Fragments by VEGF-C Treatment

Secondary lymphedema is a common complication after removal of lymph nodes in combination with radiation therapy in the treatment of breast cancer, cervical cancer, and melanomas. Only symptomatic therapies are available at the moment, and lymphedema is for most patients a lifelong condition involving psychological and physical disabilities. Animal models exist to study the pathophysiology of lymphedema but not to study surgical treatments. The aim of this study was to show that regeneration of autologous transplanted lymph node fragments is possible in rats that were irradiated previously locally in the groin and to examine the effects of vascular endothelial growth factor (VEGF)‐C injections on the rate of regeneration of transplanted lymph nodes. In all of the animals, inguinal and popliteal lymph nodes and adjacent lymphatic vessels were unilaterally removed and the inguinal region irradiated by a single dose of 15 Gy. Afterward, lymph node fragments were transplanted subcutaneously in the irradiated region. Half of the animals were treated by local VEGF‐C injections after transplantation. Four weeks after transplantation, drainage of the leg was tested by injection of blue dye, and the transplanted fragments were removed and examined immunohistologically. We could show that regeneration of autologous transplanted lymph node fragments is possible in areas treated with radiotherapy in the rat. We also documented that transplants can achieve a connection to the lymphatic collectors of the leg. The results suggest that the outcome of regeneration can be improved by injection of VEGF‐C in the transplantation area. Thus, lymph node fragment regeneration may be relevant for lymphedema prevention and therapy. Anat Rec, 2012.