Oliver Micke

Management of adult patients with Langerhans cell histiocytosis: recommendations from an expert panel on behalf of Euro-Histio-Net

Langerhans Cell Histiocytosis (LCH) is an orphan disease of clonal dendritic cells which may affect any organ of the body. Most of the knowledge about the diagnosis and therapy is based on pedriatic studies. Adult LCH patients are often evaluated by physicians who focus on only the most obviously affected organ without sufficient evaluation of other systems, resulting in patients being underdiagnosed and/or incompletely staged. Furthermore they may be treated with pediatric-based therapies which are less effective and sometimes more toxic for adults. The published literature on adult LCH cases lacks a comprehensive discussion on the differences between pediatric and adult patients and there are no recommendations for evaluation and comparative therapies. In order to fill this void, a number of experts in this field cooperated to develop the first recommendations for management of adult patients with LCH. Key questions were selected according to the clinical relevance focusing on diagnostic work up, therapy, and follow up. Based on the available literature up to December 2012, recommendations were established, drafts were commented by the entire group, and redrafted by the executive editor. The quality of evidence of the recommendations is predominantly attributed to the level of expert opinion. Final agreement was by consensus.

Selenium in the treatment of radiation-associated secondary lymphedema

PURPOSE The aim of this explorative study was to evaluate the impact of selenium in the treatment of lymphedema after radiotherapy. MATERIALS AND METHODS Between June 1996 and June 2001, 12 patients with edema of the arm and 36 patients with edema of the head-and-neck region were treated with selenium for therapy-related lymphedema. Of these 36 patients, 20 had interstitial endolaryngeal edema associated with stridor and dyspnea. All patients received sodium selenite over 4 to 6 weeks. RESULTS Self-assessment using a visual analog scale (n = 48) showed a reduction of 4.3 points when comparing pre- and posttreatment values (p < 0.05). Of 20 patients with endolaryngeal edema, 13 underwent no tracheostomy, 5 underwent a temporary tracheostomy, and only 2 underwent a permanent tracheostomy. Ten of 12 patients with arm edema showed a circumference reduction of the edematous limb and improvement in the Skin-Fold Index by 23.3 points. An improvement of one stage or more was shown by the Földi or the Miller score (n = 28) in 22 (Földi score) and in 24 (Miller score) patients. CONCLUSIONS Treatment with sodium selenite is well tolerated and easy to deliver. Additionally, our results suggest that sodium selenite has a positive effect on secondary-developing lymphedema caused by radiation therapy alone or by irradiation after surgery.

CONSENSUS GUIDELINES FOR RADIATION THERAPY OF BENIGN DISEASES: A MULTICENTER APPROACH IN GERMANY

PURPOSE To overcome the lack of written guidelines for radiation therapy (RT) of benign diseases, the German Working Group on Radiotherapy of Benign Diseases initiated a consensus process in 1999 to warrant continuous quality assurance and outcome research in this field. METHODS An expert panel was convened to define key issues and develop written guidelines for RT of benign diseases. Pertinent information and data from published literature were reviewed, and data of most importance were identified. In addition, a patterns of care study was conducted to obtain a nationwide survey on the current status and treatment standards. RESULTS From the data gathered, the expert panel prepared a first consensus statement that was open to propositions and comments from all participating institutions. After completion of the multicenter discussion, a final written consensus statement was compiled, discussed, and finally agreed on during a national conference of radiation therapists. For each individual nonmalignant disease, the accepted RT concepts were documented. Finally, specific evaluation tools and recommendations for follow-up examinations were defined. CONCLUSIONS For the first time, written consensus guidelines for RT of nonmalignant diseases have been developed by the interaction of all institutions involved. These guidelines may serve as a starting point for quality assessment, prospective clinical trials, and outcome research.

Radiation prophylaxis for heterotopic ossification about the hip joint—a multicenter study

PURPOSE Prophylactic radiotherapy (RT) can prevent ectopic bone formation about the hip after total hip arthroplasty. The German Cooperative Group on Radiotherapy for Benign Diseases conducted a patterns of care study about this indication addressing the involved institutions, RT dose concepts, clinical handling, and treatment outcome of prophylactic RT about the hip joint. METHODS AND MATERIALS In 1999, a patterns of care study was conducted in all German institutions to analyze the accrual pattern, number of patients, and different indications for the use and performance of prophylactic RT about the hip. The applied RT concepts of prophylactic RT were evaluated with regard to the RT technique, timing of RT (pre- or postoperative), RT dose prescription (median, range of single and total doses), and treatment outcome. All institutions were asked about the radiologic and functional failure rates at least 1 year after the completion of RT using the established radiologic (Brooker) and functional (Harris) scores with objective and subjective evaluation components. RESULTS One hundred fourteen institutions reported their clinical experience with prophylactic RT for the prevention of heterotopic ossification about the hip joint: 70 community hospitals, 23 university hospitals, and 21 private RT practices. In 1999, 5677 patients (5989 hips) had received prophylactic RT. The median number per institution was 36 patients (range 8-240). The interdisciplinary referral included orthopedic surgery (89 institutions; 3763 patients), trauma surgery (82 institutions; 1611 patients), or other disciplines (8 institutions; 298 patients). Preoperative RT was applied in 53 institutions 0.5-24 h before surgery, and postoperative RT was applied in 54 institutions 1-120 h after surgery. Most patients received 1 x 7 Gy either pre- or postoperatively. The total dose range was 5-10 Gy (preoperative RT) or 5-16 Gy (postoperative RT); the median total RT dose of both RT concepts was 7 Gy. Cobalt-60 (n = 15), linear accelerators (n = 95), and a few lower energy units (n = 4) were used. Bony structures or prostheses were shielded with standard blocks in 31 and with individual blocks in 27 institutions. Long-term clinical evaluation was available in 30 institutions from 4377 hips. Of those, 475 (11%) developed radiologic failures according to Brookers criteria. Functional hip evaluation was available in 5 institutions from 685 hips. Of those, 34 (5%) had functional failures according to the criteria of Harris. No difference in outcome was found between pre- and postoperative RT, but was with regard to the patients referral and the timing of RT. The patients who were treated >8 h before surgery or >72 h after surgery experienced a higher radiologic failure rate; radiologic failures were an important precondition for functional failures (p <0.05). CONCLUSION This patterns of care study comprises the largest number of cases reported for prophylactic hip RT to date. The results reveal that both preoperative (within 24 h) and postoperative RT (within 72 h) are effective in preventing heterotopic ossification after hip surgery. Both RT concepts achieved a similar low radiologic and functional failure rate. Single-dose RT concepts, especially, can be recommended as an excellent treatment alternative for patients with contraindications to long-term steroid or nonsteroidal anti-inflammatory agents, and this approach has become standard in most German RT institutions.

Radiation Therapy for Nonmalignant Diseases in Germany Current Concepts and Future Perspectives

Background:Radiotherapy (RT) of nonmalignant diseases has a long-standing tradition in Germany. Over the past decade significant theoretical and clinical progress has been made in this field to be internationally recognized as an important segment of clinical RT. This development is reflected in a national patterns-of-care study (PCS) conducted during the years 2001–2002.Material and Methods:In 2001 and 2002, a questionnaire was mailed to all RT facilities in Germany to assess equipment, patient accrual, RT indications, and treatment concepts. 146 of 180 institutions (81%) returned all requested data: 23 university hospitals (UNI), 95 community hospitals (COM), and 28 private institutions (PRIV). The specific diseases treated at each institution and the RT concepts were analyzed for frequencies and ratios between the different institution types. All data were compared to the first PCS in 1994–1996.Results:In 137 institutions (94%) 415 megavoltage units (mean 1.7; range 1–4), and in 78 institutions (53%) 112 orthovoltage units (mean 1.1; range 0–2) were available. A mean of 37,410 patients were treated per year in all institutions: 503 (1.3%) for inflammatory disorders, 23,752 (63.5%) for degenerative, 1,252 (3.3%) for hypertrophic, and 11,051 (29.5%) for functional, other and unspecified disorders. In comparison to the first PCS there was a significant increase of patients per year (from 20,082 to 37,410; +86.3%) in most nonmalignant diseases during the past 7–8 years. Most disorders were treated in accordance with the national consensus guidelines: the prescribed dose concepts (single and total doses) varied much less during the period 2001–2002 in comparison with the previous PCS in 1994–1996. Only five institutions (3.4%) received recommendations to change single or total doses and/or treatment delivery. Univariate analysis detected significant institutional differences in the use of RT for various disorders.Conclusion:RT is increasingly accepted in Germany as a reasonable treatment option for many nonmalignant diseases. The long-term perspective and research plan will have to include various updates of PCS, rewriting of consensus guidelines, introduction of registries for rare nonmalignant disorders, and clinical controlled studies even for so-called established indications, as international acceptance is based on the criteria of evidence-based medicine.Hintergrund:Die Radiotherapie (RT) nichtmaligner Erkrankungen hat eine lange Tradition in Deutschland. Im letzten Jahrzehnt wurden theoretische und klinische Fortschritte gemacht, die diesem Bereich der RT auch international eine erhebliche Bedeutung verschafft haben. Die positive Entwicklung stützt die jüngste Patterns-of-Care-Studie (PCS) der Jahre 2001–2002. Material und Methodik:Im Jahr 2001 und 2002 wurden anhand eines Fragebogens an allen deutschen strahlentherapeutischen Institutionen die technische Ausstattung, Patientenzuweisung, Indikationen und RT-Konzepte bei nichtmalignen Erkrankungen erfasst. 146 von 180 Institutionen (81%) machten vollständige Angaben: 23 Universitätskliniken (UNI), 95 Versorgungskrankenhäuser (COM) und 28 private Praxen (PRIV). Die einzelnen Krankheitsgruppen und Erkrankungen pro Institution und die RT-Konzepte wurden nach Häufigkeit und Verhältnis zwischen den Institutionen analysiert und mit der ersten PCS aus den Jahren 1994–1996 verglichen.Ergebnisse:In 137 Institutionen (94%) standen 415 Megavolt-Geräte (Mittel 1,7; Spanne 1–4) und in 78 Institutionen (53%) 112 Orthovolt-Geräte (Mittel 1,1; Spanne 0–2) zur Verfügung. Im Mittel wurden insgesamt 37 410 Patienten pro Jahr behandelt: 503 (1,3%) wegen entzündlicher, 23 752 (63,5%) wegen degenerativer, 1 252 (3,3%) wegen hyperproliferativer und 11 051 (29,5%) wegen funktioneller, anderer und nicht spezifizierter Erkrankungen. Im Vergleich zur ersten PCS vor 7–8 Jahren stieg die Patientenzahl pro Jahr signifikant an (von 20 082 auf 37 410; +86,3%). Die meisten Erkrankungen wurden gemäß den nationalen Konsensus-Leitlinien behandelt: Die Dosierungskonzepte (Einzel- und Gesamtdosis) schwankten im Zeitabschnitt 2001–2002 weit weniger als bei der vorherigen PCS von 1994–1996. Nur fünf Institutionen (3,4%) wurde aufgrund der eingereichten Daten eine Änderung der Einzel- und Gesamtdosis oder der Bestrahlungstechnik empfohlen. Es fanden sich univariat statistisch signifikante Unterschiede zwischen den einzelnen Institutionen und Krankheitsgruppen.Schlussfolgerung:Die RT wird in Deutschland zunehmend als Behandlungsoption für viele nichtmaligne Erkrankungen akzeptiert. Die langfristige Perspektive und Forschung auf diesem Gebiet müssen neben der Aktualisierung von PCS auch die Überarbeitung der Konsensus-Leitlinien, die Einführung von Registern für seltene Erkrankungen und die Durchführung kontrollierter Studien auch bei „etablierten Indikationen“ zum Ziel haben, da die internationale Akzeptanz allein auf den Kriterien der evidenzbasierten Medizin aufbaut.

Predictive value of carbohydrate antigen 19-9 in pancreatic cancer treated with radiochemotherapy

PURPOSE To determine the predictive value of carbohydrate antigen (CA) 19-9 in pancreatic cancer treated with radiochemotherapy. METHODS AND MATERIALS Ninety-five patients with locally advanced unresectable adenocarcinoma of the pancreas were treated with hyperfractionated accelerated radiotherapy to a total dose of 44.8 Gy combined with 5-fluorouracil and folinic acid. CA 19-9 was measured before therapy, each week during therapy, and every 4 weeks during the follow-up period. RESULTS The median CA 19-9 before treatment was 420 U/mL; in the responder group it was 117 U/mL, and in the nonresponder group it was 806 U/mL. Patients with a pretreatment CA 19-9 less than the median had not only a significantly better tumor response (45.8%) but also a better survival prognosis (median survival 12.3 months) than those with a level higher than the median (tumor response 12.8%; median survival 7.1 months). The posttreatment median CA 19-9 for all patients also exhibited prognostic significance. The median survival of patients with a CA 19-9 level lower than the posttreatment median of 293 U/mL was 13.5 months, compared with 7.2 months for those with a CA 19-9 level greater than the median. To detect recurrent disease during follow-up, the sensitivity of CA 19-9 was 100% and the specificity 88%. CONCLUSION Our results indicate that CA 19-9 is of predictive value for prognosis, response, and detecting recurrence of pancreatic cancer in patients undergoing combined radiochemotherapy. Therefore, we recommend the routine implementation of CA 19-9 observation during the clinical course of treatment for patients with pancreatic cancer undergoing radiochemotherapy.

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.

RADIOTHERAPY IN PAINFUL HEEL SPURS (PLANTAR FASCIITIS)—RESULTS OF A NATIONAL PATTERNS OF CARE STUDY

PURPOSE After a general patterns of care study, the German Cooperative Group on Radiotherapy for Benign Diseases conducted a multicenter cohort study to analyze radiotherapy (RT) in painful heel spur syndrome (HSS). METHODS AND MATERIALS In 2001, a patterns of care study was conducted in all German RT institutions using a standardized structured questionnaire. Patient accrual, patient number, pretreatment, pain record, treatment indications, RT technique, and target volume concepts for painful HSS were assessed. In addition, the functional and subjective outcomes were evaluated. RESULTS Of the institutions, 146 (79.3%) returned the questionnaire: 10 (6.8%) reported no clinical experience with RT for HSS, and 136 (93.2%) treated 3621 patients annually, a median of 23 cases/institution. The indications for treatment were chronic or therapy refractory pain. The total dose ranged between 2.5 and 18.75 Gy (median 6), and single fractions ranged between 0.3 and 1. 5 Gy (median 1). Of the responding institutions, 44.9% applied two fractions and 37.5% three fractions weekly. RT was delivered with orthovoltage units (38.2%), linear accelerators (53.7%), (60)Co units (5.1%), or other treatment units (3%). Seventy-six institutions presented their retrospective clinical evaluation in a total of 7947 patients. Pain reduction for at least 3 months was reported in 70%, and persistent pain reduction was reported in 65% of the treated patients. In 19 institutions, a second RT series was applied for inadequate pain response or early pain recurrence. No radiogenic acute or chronic side effects were observed. CONCLUSION The study comprised the largest number of cases reported of RT for painful HSS. Despite variations in the daily RT practice, this national patterns of care study represents a very large number of painful and refractory HSS cases that were treated effectively with RT.

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.

Radiation Therapy for Nonmalignant Diseases in Germany

Background:Radiotherapy (RT) of nonmalignant diseases has a long-standing tradition in Germany. Over the past decade significant theoretical and clinical progress has been made in this field to be internationally recognized as an important segment of clinical RT. This development is reflected in a national patterns-of-care study (PCS) conducted during the years 2001–2002.Material and Methods:In 2001 and 2002, a questionnaire was mailed to all RT facilities in Germany to assess equipment, patient accrual, RT indications, and treatment concepts. 146 of 180 institutions (81%) returned all requested data: 23 university hospitals (UNI), 95 community hospitals (COM), and 28 private institutions (PRIV). The specific diseases treated at each institution and the RT concepts were analyzed for frequencies and ratios between the different institution types. All data were compared to the first PCS in 1994–1996.Results:In 137 institutions (94%) 415 megavoltage units (mean 1.7; range 1–4), and in 78 institutions (53%) 112 orthovoltage units (mean 1.1; range 0–2) were available. A mean of 37,410 patients were treated per year in all institutions: 503 (1.3%) for inflammatory disorders, 23,752 (63.5%) for degenerative, 1,252 (3.3%) for hypertrophic, and 11,051 (29.5%) for functional, other and unspecified disorders. In comparison to the first PCS there was a significant increase of patients per year (from 20,082 to 37,410; +86.3%) in most nonmalignant diseases during the past 7–8 years. Most disorders were treated in accordance with the national consensus guidelines: the prescribed dose concepts (single and total doses) varied much less during the period 2001–2002 in comparison with the previous PCS in 1994–1996. Only five institutions (3.4%) received recommendations to change single or total doses and/or treatment delivery. Univariate analysis detected significant institutional differences in the use of RT for various disorders.Conclusion:RT is increasingly accepted in Germany as a reasonable treatment option for many nonmalignant diseases. The long-term perspective and research plan will have to include various updates of PCS, rewriting of consensus guidelines, introduction of registries for rare nonmalignant disorders, and clinical controlled studies even for so-called established indications, as international acceptance is based on the criteria of evidence-based medicine.Hintergrund:Die Radiotherapie (RT) nichtmaligner Erkrankungen hat eine lange Tradition in Deutschland. Im letzten Jahrzehnt wurden theoretische und klinische Fortschritte gemacht, die diesem Bereich der RT auch international eine erhebliche Bedeutung verschafft haben. Die positive Entwicklung stützt die jüngste Patterns-of-Care-Studie (PCS) der Jahre 2001–2002. Material und Methodik:Im Jahr 2001 und 2002 wurden anhand eines Fragebogens an allen deutschen strahlentherapeutischen Institutionen die technische Ausstattung, Patientenzuweisung, Indikationen und RT-Konzepte bei nichtmalignen Erkrankungen erfasst. 146 von 180 Institutionen (81%) machten vollständige Angaben: 23 Universitätskliniken (UNI), 95 Versorgungskrankenhäuser (COM) und 28 private Praxen (PRIV). Die einzelnen Krankheitsgruppen und Erkrankungen pro Institution und die RT-Konzepte wurden nach Häufigkeit und Verhältnis zwischen den Institutionen analysiert und mit der ersten PCS aus den Jahren 1994–1996 verglichen.Ergebnisse:In 137 Institutionen (94%) standen 415 Megavolt-Geräte (Mittel 1,7; Spanne 1–4) und in 78 Institutionen (53%) 112 Orthovolt-Geräte (Mittel 1,1; Spanne 0–2) zur Verfügung. Im Mittel wurden insgesamt 37 410 Patienten pro Jahr behandelt: 503 (1,3%) wegen entzündlicher, 23 752 (63,5%) wegen degenerativer, 1 252 (3,3%) wegen hyperproliferativer und 11 051 (29,5%) wegen funktioneller, anderer und nicht spezifizierter Erkrankungen. Im Vergleich zur ersten PCS vor 7–8 Jahren stieg die Patientenzahl pro Jahr signifikant an (von 20 082 auf 37 410; +86,3%). Die meisten Erkrankungen wurden gemäß den nationalen Konsensus-Leitlinien behandelt: Die Dosierungskonzepte (Einzel- und Gesamtdosis) schwankten im Zeitabschnitt 2001–2002 weit weniger als bei der vorherigen PCS von 1994–1996. Nur fünf Institutionen (3,4%) wurde aufgrund der eingereichten Daten eine Änderung der Einzel- und Gesamtdosis oder der Bestrahlungstechnik empfohlen. Es fanden sich univariat statistisch signifikante Unterschiede zwischen den einzelnen Institutionen und Krankheitsgruppen.Schlussfolgerung:Die RT wird in Deutschland zunehmend als Behandlungsoption für viele nichtmaligne Erkrankungen akzeptiert. Die langfristige Perspektive und Forschung auf diesem Gebiet müssen neben der Aktualisierung von PCS auch die Überarbeitung der Konsensus-Leitlinien, die Einführung von Registern für seltene Erkrankungen und die Durchführung kontrollierter Studien auch bei „etablierten Indikationen“ zum Ziel haben, da die internationale Akzeptanz allein auf den Kriterien der evidenzbasierten Medizin aufbaut.