Angelika Zabel-du Bois

Fractionated stereotactic radiation therapy in the management of benign cavernous sinus meningiomas : Long-term experience and review of the literature

Purpose:To analyze own long-term results with fractionated stereotactic radiotherapy (FSRT) in patients with benign meningiomas of the cavernous sinus and to review the literature on these rare lesions.Patients and Methods:57 patients were treated with FSRT for benign meningiomas of the cavernous sinus between 01/1990 and 12/2003 at the authors’ institution. Histology was WHO grade I in 28/57 lesions, and undetermined in 29/57 lesions. 29 patients received radiotherapy as primary treatment, ten following surgery, and 18 patients were irradiated for recurrent disease. Median target volume was 35.2 cm3. Median total dose was 57.6 Gy with 1.8 Gy per fraction. 51/57 patients showed clinical symptoms before radiotherapy like reduced vision (n = 19), diplopia (n = 25), or trigeminal hyp-/dysesthesia (n = 17).Results:Median follow-up period was 6.5 years. 50/57 patients were followed for > 36 months. Overall local tumor control was 100%. 39/57 patients had stable disease based on CT/MRI, while 18/57 had a partial remission of tumor volume. Overall survival for patients with WHO grade I meningiomas was 95.5% after 5 and 10 years. Two patients died 2.8 and 4.1 years after radiotherapy due to cardiac failure. In 11/57 patients, preexisting neurologic deficits improved. There was one patient with recurrent hyperlacrimation of one eye on the side of the irradiated meningioma. Three patients complained about subjective visual deterioration after FSRT without any objective findings in an ophthalmologic examination. No late toxicity RTOG ≥ °III was seen.Conclusion:These data demonstrate that FSRT is an effective and safe treatment modality for local control of benign cavernous sinus meningiomas with a minimal risk of significant late toxicity.Ziel:Darstellung der Langzeitergebnisse nach fraktionierter stereotaktischer Strahlentherapie (FSRT) von benignen Sinus-cavernosus-Meningeomen und Literaturübersicht dieser seltenen Befunde.Patienten und Methodik:Zwischen 01/1990 und 12/2003 wurden 57 Patienten mittels FSRT an einem benignen Sinus-cavernosus-Meningeom in der Abteilung der Autoren behandelt. Histopathologisch entsprachen 28/57 Befunde WHO-Grad I, und 29/57 Befunde waren ausschließlich bildmorphologisch eindeutig als Meningeom diagnostiziert worden. 29 Patienten wurden primär, zehn postoperativ und 18 in einer Rezidivsituation bestrahlt. Die mediane Zielvolumengröße betrug 35,2 cm3. Die mediane applizierte Gesamtdosis betrug 57,6 Gy bei einer wöchentlichen Fraktionierung von 5 × 1,8 Gy. Initial zeigten 51/57 Patienten neurologische Symptome, wie Sehverschlechterung (n = 19), Doppelbilder (n = 25) oder Trigeminushyp-/-dysästhesie (n = 17).Ergebnisse:Die lokale Tumorkontrollrate betrug 100% nach einer medianen Nachbeobachtungszeit von 6,5 Jahren. Bei 50/57 Patienten war der Nachbeobachtungszeitraum > 36 Monate. 39 Meningeome zeigten eine Größenkonstanz im CT/MRT, 18 Befunde eine Größenreduktion. Das Gesamtüberleben betrug 95,5% nach 5 und 10 Jahren. Zwei Patienten verstarben 2,8 und 4,1 Jahre nach Strahlentherapie an kardialer Ursache. Bei 11/57 Patienten zeigte sich nach Strahlentherapie eine deutliche Besserung der vorbestehenden neurologischen Symptomatik. Ein Patient entwickelte im Verlauf rezidivierendes Augentränen auf der Seite des bestrahlten Meningeoms. Drei Patienten berichteten über rezidivierende subjektive Sehverschlechterung ohne ophthalmologisches Korrelat. Es traten keine Spättoxizitäten RTOG ≥ °III auf.Schlussfolgerung:Die FSRT ist sicher anwendbar und erreicht gute lokale Tumorkontrollraten bei geringem Risiko für radiogene Spätkomplikationen.

Fractionated Stereotactic Radiation Therapy in the Management of Benign Cavernous Sinus Meningiomas

Purpose:To analyze own long-term results with fractionated stereotactic radiotherapy (FSRT) in patients with benign meningiomas of the cavernous sinus and to review the literature on these rare lesions.Patients and Methods:57 patients were treated with FSRT for benign meningiomas of the cavernous sinus between 01/1990 and 12/2003 at the authors’ institution. Histology was WHO grade I in 28/57 lesions, and undetermined in 29/57 lesions. 29 patients received radiotherapy as primary treatment, ten following surgery, and 18 patients were irradiated for recurrent disease. Median target volume was 35.2 cm3. Median total dose was 57.6 Gy with 1.8 Gy per fraction. 51/57 patients showed clinical symptoms before radiotherapy like reduced vision (n = 19), diplopia (n = 25), or trigeminal hyp-/dysesthesia (n = 17).Results:Median follow-up period was 6.5 years. 50/57 patients were followed for > 36 months. Overall local tumor control was 100%. 39/57 patients had stable disease based on CT/MRI, while 18/57 had a partial remission of tumor volume. Overall survival for patients with WHO grade I meningiomas was 95.5% after 5 and 10 years. Two patients died 2.8 and 4.1 years after radiotherapy due to cardiac failure. In 11/57 patients, preexisting neurologic deficits improved. There was one patient with recurrent hyperlacrimation of one eye on the side of the irradiated meningioma. Three patients complained about subjective visual deterioration after FSRT without any objective findings in an ophthalmologic examination. No late toxicity RTOG ≥ °III was seen.Conclusion:These data demonstrate that FSRT is an effective and safe treatment modality for local control of benign cavernous sinus meningiomas with a minimal risk of significant late toxicity.Ziel:Darstellung der Langzeitergebnisse nach fraktionierter stereotaktischer Strahlentherapie (FSRT) von benignen Sinus-cavernosus-Meningeomen und Literaturübersicht dieser seltenen Befunde.Patienten und Methodik:Zwischen 01/1990 und 12/2003 wurden 57 Patienten mittels FSRT an einem benignen Sinus-cavernosus-Meningeom in der Abteilung der Autoren behandelt. Histopathologisch entsprachen 28/57 Befunde WHO-Grad I, und 29/57 Befunde waren ausschließlich bildmorphologisch eindeutig als Meningeom diagnostiziert worden. 29 Patienten wurden primär, zehn postoperativ und 18 in einer Rezidivsituation bestrahlt. Die mediane Zielvolumengröße betrug 35,2 cm3. Die mediane applizierte Gesamtdosis betrug 57,6 Gy bei einer wöchentlichen Fraktionierung von 5 × 1,8 Gy. Initial zeigten 51/57 Patienten neurologische Symptome, wie Sehverschlechterung (n = 19), Doppelbilder (n = 25) oder Trigeminushyp-/-dysästhesie (n = 17).Ergebnisse:Die lokale Tumorkontrollrate betrug 100% nach einer medianen Nachbeobachtungszeit von 6,5 Jahren. Bei 50/57 Patienten war der Nachbeobachtungszeitraum > 36 Monate. 39 Meningeome zeigten eine Größenkonstanz im CT/MRT, 18 Befunde eine Größenreduktion. Das Gesamtüberleben betrug 95,5% nach 5 und 10 Jahren. Zwei Patienten verstarben 2,8 und 4,1 Jahre nach Strahlentherapie an kardialer Ursache. Bei 11/57 Patienten zeigte sich nach Strahlentherapie eine deutliche Besserung der vorbestehenden neurologischen Symptomatik. Ein Patient entwickelte im Verlauf rezidivierendes Augentränen auf der Seite des bestrahlten Meningeoms. Drei Patienten berichteten über rezidivierende subjektive Sehverschlechterung ohne ophthalmologisches Korrelat. Es traten keine Spättoxizitäten RTOG ≥ °III auf.Schlussfolgerung:Die FSRT ist sicher anwendbar und erreicht gute lokale Tumorkontrollraten bei geringem Risiko für radiogene Spätkomplikationen.

Radiochemotherapy in Patients With Primary Glioblastoma Comparing Two Temozolomide Dose Regimens

PURPOSE To evaluate toxicity and outcomes in patients with primary glioblastoma (GB) treated with postoperative radiochemotherapy (RCHT) with temozolomide (TMZ) comparing two dose regimens. METHODS AND MATERIALS A total of 160 patients with histologically confirmed GB were treated with postoperative RCHT with TMZ. Of the patients, 66 were female and 94 were male, with a median age of 60 years. After the primary diagnosis, a biopsy had been performed in 42 patients; a subtotal and total resection was conducted in 66 and 52 patients. Postoperative radiotherapy was applied with a median dose of 60 Gy with a median fractionation of 5 x 2Gy/week. Concomitant TMZ was prescribed at 50 mg/m(2) in 123 patients (Group A) and at 75 mg/m(2) in 37 patients (Group B). Patients were followed in 3-months intervals, with a median follow-up of 13 months. RESULTS Overall survival (OS) rates in Group A vs. Group B were 67% and 79% at 1 year and 43% vs. 49% at 2 years, respectively (p = 0.69). Progression-free survival was 49% vs. 54% at 1 year and 22% vs. 29% at 2 years (p = 0.31). Hematologic toxicity was not statistically significant over the 6-week RCHT period except for a significant decrease in platelets during Week 6 (p = 0.01) in Group B. CONCLUSIONS Overall survival seems to be comparable in both groups, although longer follow-up and a larger group of patients are needed to corroborate these results. Lower dosing of TMZ also is associated with a more beneficial toxicity profile.

Intensity modulated radiotherapy in the management of sacral chordoma in primary versus recurrent disease

PURPOSE To investigate treatment outcome in patients suffering from sacral chordoma after intensity modulated radiotherapy (IMRT) for primary versus recurrent disease. MATERIAL/METHODS We report on 34 patients with histologically proven sacral chordoma. Seventeen patients were treated at time of initial diagnosis with post-operative IMRT (n=13) or with IMRT alone (n=4). Seventeen patients were treated in recurrent disease after surgery (n=11) or with radiotherapy alone (n=6). Median total dose to the boost volume (PTV2) was 66 Gy (range, 72-54) with 2 Gy per fraction using an integrated boost concept. Median dose to target volume (PTV1) was 54 Gy in 1.8 Gy. RESULTS Local control was 35% (12/34) and overall survival 74% (25/34) after a median follow-up of 4.5 years. Actuarial local control was 79%, 55% and 27% after 1, 2 and 5 years, respectively. Local control was significantly higher in patients treated for primary tumors (p<0.03) and in total doses >60 Gy (p<0.01). Actuarial overall survival was 97%, 91% and 70% after 1, 2 and 5 years, respectively. CONCLUSION These data demonstrate that local control after IMRT is higher in patients treated for primary tumors and using higher radiation doses. Therefore, we recommend radiotherapy as part of initial treatment in sacral chordoma.

Multidisciplinary pain management based on a computerized clinical decision support system in cancer pain patients

ABSTRACT A prospective controlled intervention cohort study in cancer pain patients (n = 50 per group) admitted to radiation oncology wards (62 beds, 3 wards) was conducted in a 1621‐bed university hospital. We investigated the effect of an intervention consisting of daily pain assessment using the numeric visual analog scale (NVAS) and pain therapy counseling to clinicians based on a computerized clinical decision support system (CDSS) to correct deviations from pain therapy guidelines. Effects on guideline adherence (primary outcome), pain relief (NVAS) at rest and during physical activity (both groups: cross‐sectional assessment on day 5; intervention group: every day assessment), co‐analgesic prescription, and acceptance rates of recommendations (secondary outcomes) were assessed. The number of patients with at least one deviation from guidelines at discharge was decreased by the intervention from 37 (74%) in controls to 7 (14%, p < 0.001). In the intervention group, pain (NVAS) decreased during hospital stay at rest from 3.0 (Δ0.5 (Q75% − Q25%) = 3.0) on admission to 1.5 (Δ0.5 = 1.0) at discharge (p < 0.01) and during physical activity from 7.0 (Δ0.5 = 4.0) on admission to 2.5 (Δ0.5 = 3.8) at discharge (p < 0.001). At discharge, the number of patients treated with co‐analgesics increased from 23 (46%) in controls to 33 (66%) in the intervention group (p = 0.04). From 279 recommendations issued in the intervention 85% were fully accepted by the physicians. Deviations from well‐established guidelines are frequent in pain therapy. A multidisciplinary pain management increased adherence to pain management guidelines.

New multileaf collimator with a leaf width of 5 mm improves plan quality compared to 10 mm in step-and-shoot IMRT of HNC using integrated boost procedure

Purpose:To investigate whether a new multileaf collimator with a leaf width of 5 mm (MLC-5) over the entire field size of 40 × 40 cm2 improves plan quality compared to a leaf width of 10 mm (MLC-10) in intensity-modulated radiotherapy (IMRT) with integrated boost for head and neck cancer.Patients and Methods:A plan comparison was performed for ten patients with head and neck cancer. For each patient, seven plans were calculated: one plan with MLC-10 and nine beams, four plans with MLC-5 and nine beams (with different intensity levels and two-dimensional median filter sizes [2D-MFS]), and one seven-beam plan with MLC-5 and MLC-10, respectively. Isocenter, beam angles and planning constraints were not changed. Mean values of common plan parameters over all ten patients were estimated, and plan groups of MLC-5 and MLC-10 with nine and seven beams were compared.Results:The use of MLC-5 led to a significantly higher conformity index and an improvement of the 90% coverage of PTV1 (planning target volume) and PTV2 compared with MLC-10. This was noted in the nine- and seven-beam plans. Within the nine-beam group with MLC-5, a reduction of the segment number by up to 25% at reduced intensity levels and for increased 2D-MFS did not markedly worsen plan quality. Interestingly, a seven-beam IMRT with MLC-5 was inferior to a nine-beam IMRT with MLC-5, but superior to a nine-beam IMRT with MLC-10.Conclusion:The use of an MLC-5 has significant advantages over an MLC-10 with respect to target coverage and protection of normal tissues in step-and-shoot IMRT of head and neck cancer.Ziel:Gegenstand dieser Untersuchung war, ob bei der intensitätsmodulierten Radiotherapie (IMRT) von Kopf-Hals-Tumoren mit integriertem Boost ein neuer kommerzieller Multileafkollimator mit einer Lamellenblende von 5 mm (MLC-5) über eine Feldgröße von 40 × 40 cm2 zu einer Verbesserung der Planqualität im Vergleich zu einer Lamellenblende von 10 mm (MLC-10) führt.Patienten und Methodik:Der Planvergleich wurde an zehn Patienten mit Kopf-Hals-Tumoren durchgeführt. Für jeden Patienten wurden sieben Pläne berechnet: ein Plan mit MLC-10 und neun Feldern, vier Pläne mit MLC-5 und neun Feldern (mit verschiedenen Intensitätsleveln bzw. zweidimensionalen Medianfiltergrößen [2D-MFS]) und je ein Sieben-Felder-Plan mit MLC-5 und MLC-10. Isozentrum, Feldwinkel und Planungsbeschränkungen blieben unverändert. Es wurden Mittelwerte der üblichen Planparameter von allen zehn Patienten berechnet und die Plangruppen mit MLC-5 und MLC-10 bzw. neun und sieben Feldern miteinander verglichen.Ergebnisse:Der Einsatz eines MLC-5 führt im Vergleich zu einem MLC-10 zu einer signifikanten Verbesserung des Konformitätsindex und zu einer Erhöhung von V90 des PTV1 (Planungszielvolumen) und PTV2 (Tabellen 1–4, Abbildung 3). Dies konnte für Neun- und Sieben-Felder-Pläne gezeigt werden. Innerhalb der Neun-Felder-Plangruppen mit MLC-5 führte eine Verringerung der Segmentanzahl um 25% durch Reduktion der Intensitätslevel und/oder des 2D-MFS nicht zu einer Verschlechterung der Planqualität (Abbildung 2). Eine Sieben-Felder-IMRT mit MLC-5 war einer Neun-Felder-IMRT mit MLC-5 unterlegen, aber besser als eine Neun-Felder-IMRT mit MLC-10.Schlussfolgerung:Die Verwendung eines MLC-5 weist gegenüber einem MLC-10 signifikante Vorteile bezüglich der Zielvolumenabdeckung und der Normalgewebsschonung bei der „step-and-shoot“-IMRT von Kopf-Hals-Tumoren mit integrierter Boostapplikation auf.

Proposal for a new prognostic score for linac-based radiosurgery in cerebral arteriovenous malformations.

PURPOSE We evaluate patient-, angioma-, and treatment-specific factors for successful obliteration of cerebral arteriovenous malformations (AVM) to develop a new appropriate score to predict patient outcome after linac-based radiosurgery (RS). METHODS AND MATERIALS This analysis in based on 293 patients with cerebral AVM. Mean age at treatment was 38.8 years (4-73 years). AVM classification according Spetzler-Martin was 55 patients Grade I (20.5%), 114 Grade II (42.5%), 79 Grade III (29.5%), 19 Grade IV (7.1%), and 1 Grade V (0.4%). Median maximum AVM diameter was 3.0 cm (range, 0.3-10 cm). Median dose prescribed to the 80% isodose was 18 Gy (range, 12-22 Gy). Eighty-five patients (29.1%) had prior partial embolization; 141 patients (51.9%) experienced intracranial hemorrhage before RS. Median follow-up was 4.2 years. RESULTS Age at treatment, maximum diameter, nidus volume, and applied dose were significant factors for successful obliteration. Under presumption of proportional hazard in the dose range between 12 and 22 Gy/80% isodose, an increase of obliteration rate of approximately 25% per Gy was seen. On the basis of multivariate analysis, a prediction score was calculated including AVM maximum diameter and age at treatment. The prediction error up to the time point 8 years was 0.173 for the Heidelberg score compared with the Kaplan-Meier value of 0.192. An increase of the score of 1 point results in a decrease of obliteration chance by a factor of 0.447. CONCLUSION The proposed score is linac-based radiosurgery-specific and easy to handle to predict patient outcome. Further validation on an independent patient cohort is necessary.

Repeated linac-based radiosurgery in high-grade cerebral arteriovenous-malformations (AVM) Spetzler-Martin grade III to IV previously treated with radiosurgery

BACKGROUND Aim was to access outcome and toxicity of repeated linac-based radiosurgery in incompletely obliterated cerebral AVM. PATIENTS AND METHODS Between 1998 and 2008, 11 patients were treated with repeated radiosurgery. The median dose to the 80%-isodose was 15 Gy (range, 12-18 Gy). During initial radiosurgery the median dose was 18 Gy (range, 9-22 Gy). RESULTS The median time interval between initial radiosurgery and re-treatment was 9 years (range, 4-16 years). The median follow-up was 26 months (range, 2-115 months). Treatment response was seen in 8 patients (89%). Complete (partial) obliteration was achieved in 5 (3) patients (56%, 33%, respectively).The median time to complete obliteration was 26 months (range, 5-45 months). Pre-existing neurological symptoms improved in 2 patients (18%), were stable in 7 patients (64%) and worsened in 2 patients (18%). Prevalence of intracranial hemorrhage was 9% (1/11). Post-re-treatment intracranial hemorrhage rate was 2.7% (1/38 years at risk). During follow-up, no secondary malignancies or toxicity>grade III were observed. CONCLUSION Repeated linac-based radiosurgery in incompletely obliterated cerebral AVM is an effective treatment option with a high rate of treatment response and an acceptable risk for side effects. Marginal doses above 15 Gy might further improve the rate of complete obliterations.

Gene expression signatures in the peripheral blood after radiosurgery of human cerebral arteriovenous malformations

Purpose:To unravel biological mechanisms potentially resulting in the obliteration process after radiosurgery (RS) of human cerebral arteriovenous malformations (AVMs) by investigating molecular signatures on the transcriptomic level in peripheral blood of patients.Patients and Methods:Venous blood samples were obtained at definite points of time before and after RS. The samples were tested for radiation-induced changes regarding biological markers (mRNA) using cDNA and oligo-microarray technology. The corresponding expression profiles were correlated with clinical data and obliteration signs in radiologic imaging.Results:The proof of principle that RS outcome can be successfully correlated with transcriptomics of cellular blood components as disease parameter was demonstrated. The authors identified 76 differentially regulated genes (p < 0.001) after RS. Interestingly, in particular genes with known roles in antiangiogenic and procoagulative pathways were identified as potentially relevant. In particularly, the authors found a significant downregulation of neuropilin-2, protein C inhibitor and cyclin-dependent kinase 6. They also found that low pretreatment blood mRNA levels of TLR4 (toll-like receptor 4) and STAT3 (signal transducer and activator of transcription 3) correlated with fast obliteration of AVMs.Conclusion:The authors report on a novel technique for molecular biological analysis of blood from patients with cerebral AVM treated with RS. Differential regulation of genes in peripheral blood was successfully correlated with RS and time to obliteration of AVMs. The identified genes indicate a potential new methodology to monitor RS, which may result in an individualized therapy and optimized follow-up.Ziel:Untersucht wurden die molekularen Mechanismen der Wirkung ionisierender Strahlung auf das pathologische Gefäßkonvolut bei zerebralen arteriovenösen Malformationen (AVM) im peripheren Blut von Patienten nach Radiochirurgie (RS).Patienten und Methodik:Bei Patienten mit zerebraler AVM wurde zu definierten Zeitpunkten vor und nach RS eine venöse Blutprobe gewonnen und mittels cDNA- und Oligo-Microarray-Technologie auf strahleninduzierte Veränderungen hinsichtlich biologischer Marker (mRNA) getestet. Die entsprechenden Expressionsprofile wurden mit dem Obliterationsverlauf in der radiologischen Bildgebung verglichen.Ergebnisse:Erstmals konnte gezeigt werden, dass eine Korrelation zwischen klinischen Parametern nach RS zerebraler AVM und Genaktivität von peripheren Blutbestandteilen möglich ist. Es konnten 76 Gene als signifikant (p < 0,001) reguliert identifiziert werden. Insbesondere wurden antiangiogene Mechanismen der Strahlenwirkung sowie prokoagulatorische Effekte als funktionell relevant identifiziert. Beispielsweise zeigte sich eine signifikant verminderte Expression von Neuropilin-2 (NRP-2), Protein-C-Inhibitor (PCI) und „cyclin-dependent kinase 6“ (CDK6). Darüber hinaus konnten eine positive Korrelation zwischen niedrigen prätherapeutischen mRNA-Werten von TLR4 („toll-like receptor 4“) und STAT3 (signal transducer and activator of transcription 3) im Blut der Patienten und schneller Obliteration der AVM nachgewiesen werden.Schlussfolgerung:Durch genomweite Untersuchungen an Blutproben von Patienten mit zerebraler AVM vor und nach RS konnten erstmals molekulare Signaturen im peripheren Blut identifiziert werden. Diese erlauben möglicherweise ein biologisches Therapiemonitoring. Die unterschiedliche Genregulation im peripheren Blut nach RS konnte erfolgreich mit der Zeit bis zur Obliteration der AVM korreliert werden. Weiterführende Untersuchungen der identifizierten Gene und Proteine sollen in Zukunft eine optimierte Verlaufskontrolle nach Radiotherapie und eine individuell optimierte Behandlung ermöglichen.

SU11657 Enhances Radiosensitivity of Human Meningioma Cells

PURPOSE To analyze the effect of the multireceptor tyrosine kinase inhibitor SU11657 (primarily vascular endothelial growth factor, platelet-derived growth factor) in combination with irradiation in freshly isolated primary human meningioma cells. METHODS AND MATERIALS Tumor specimens were obtained from meningioma patients undergoing surgery at the Department of Neurosurgery, University of Heidelberg, Germany. For the present study only cells up to passage 6 were used. Benign and atypical meningioma cells and human umbilical vein endothelial cells (HUVEC) were treated with SU11657 alone and in combination with 6-MV photons (0-10 Gy). Clonogenic survival and cell proliferation were determined alone and in coculture assays to determine direct and paracrine effects. RESULTS Radiation and SU11657 alone reduced cell proliferation in atypical and benign meningioma cells as well as in HUVEC in a dose-dependent manner. SU11657 alone also reduced clonogenic survival of benign and atypical meningioma cells. SU11657 increased radiosensitivity of human meningioma cells in clonogenic survival and cell number/proliferation assays. The anticlonogenic and antiproliferative effects alone and the radiosensitization effects of SU11657 were more pronounced in atypical meningioma cells compared with benign meningioma cells. CONCLUSION Small-molecule tyrosine kinase inhibitors like SU11657 are capable of amplifying the growth inhibitory effects of irradiation in meningioma cells. These data provide a rationale for further clinical evaluation of this combination concept, especially in atypical and malignant meningioma patients.