Juergen Voges

Imaging-guided convection-enhanced delivery and gene therapy of glioblastoma.

In a prospective phase I/II clinical study, we treated eight patients suffering from recurrent glioblastoma multiform with stereotactically guided intratumoral convection‐enhanced delivery of an HSV‐1‐tk gene–bearing liposomal vector and systemic ganciclovir. Noninvasive identification of target tissue together with assessment of vector‐distribution volume and the effects of gene therapy were achieved using magnetic resonance imaging and positron emission tomography. The treatment was tolerated well without major side effects. In two of eight patients, we observed a greater than 50% reduction of tumor volume and in six of eight patients focal treatment effects. Intracerebral infusion of contrast medium before vector application displayed substantial inhomogeneity of tissue staining indicating the need of test infusions to monitor the mechanical distribution of vectors. Visualization of therapeutic effects on tumor metabolism and documentation of gene expression using positron emission tomography indicated that molecular imaging technology appears to be essential for the further development of biological treatment strategies.

Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: Evidence from a FDG-PET study in advanced Parkinson's disease

Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a highly effective surgical treatment in patients with advanced Parkinsons disease (PD). Because the STN has been shown to represent an important relay station not only in motor basal ganglia circuits, the modification of brain areas also involved in nonmotor functioning can be expected by this intervention. To determine the impact of STN-DBS upon the regional cerebral metabolic rate of glucose (rCMRGlc), we performed positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) in eight patients with advanced PD before surgery as well as in the DBS on- and off-conditions 4 months after electrode implantation and in ten age-matched healthy controls. Before surgery, PD patients showed widespread bilateral reductions of cortical rCMRGlc versus controls but a hypermetabolic state in the left rostral cerebellum. In the STN-DBS on-condition, clusters of significantly increased rCMRGlc were found in both lower thalami reaching down to the midbrain area and remote from the stimulation site in the right frontal cortex, temporal cortex, and parietal cortex, whereas rCMRGlc significantly decreased in the left rostral cerebellum. Therefore, STN-DBS was found to suppress cerebellar hypermetabolism and to partly restore physiologic glucose consumption in limbic and associative projection territories of the basal ganglia. These data suggest an activating effect of DBS upon its target structures and confirm a central role of the STN in motor as well as associative, limbic, and cerebellar basal ganglia circuits.

Linear accelerator radiosurgery for pituitary macroadenomas: a 7-year follow-up study.

A prospective study was conducted to assess the efficacy and side effects of linear accelerator (LINAC)‐based radiosurgery (RS) performed with a reduced dose of therapeutic radiation for patients with surgically inaccessible pituitary macroadenomas.

Linac radiosurgery versus whole brain radiotherapy for brain metastases. A survival comparison based on the RTOG recursive partitioning analysis.

Background and Purpose:For patients with inoperable brain metastases, whole brain radiotherapy (WBRT) has been the standard treatment for decades. Radiosurgery is an effective alternative strategy, but has failed to show a substantial survival benefit so far. The prognostic factors derived from the RTOG recursive partitioning analysis (RPA) provide a framework that allows a nonrandomized comparison of the two modalities.Patients and Methods:From 1991 to 1998, 117 patients with one to three previously untreated cerebral metastases underwent single-dose linac radiosurgery (median dose 20 Gy) without adjuvant WBRT. After radiosurgery, 26/117 patients (22%) had salvage WBRT, radiosurgery or neurosurgical resection of recurrent (4/117) and/or new (24/117) metastases. Survival of these patients was compared to a historical group of 138 patients with one to three lesions treated by WBRT (30–36 Gy/3-Gy fractions) from 1978 to 1991; only nine of these patients (7%) had salvage WBRT. All patients were classified into the three RPA prognostic classes based on age, performance score, and presence of extracranial tumor manifestations.Results:In RPA class I (Karnofsky performance score ≥ 70, primary tumor controlled, no other metastases, age < 65 years), radiosurgery resulted in a median survival of 25.4 months (n = 23, confidence interval [CI] 5.8–45.0) which was significantly longer than for WBRT (n = 9, 4.7 months, CI 3.8–5.5; p < 0.0001). In RPA class III (Karnofsky performance score < 70), no significant difference in survival between radiosurgery (n = 20, 4.2 months, CI 3.2–5.3) and WBRT (n = 68, 2.5 months, CI 2.2–2.8) was found. In RPA class II (all other patients), radiosurgery produced a small, but significant survival advantage (radiosurgery: n = 74, 5.9 months, CI 3.2–8.5, WBRT: n = 61, 4.1 months, CI 3.4–4.9; p < 0.04).Conclusion:Radiosurgery in patients with one to three cerebral metastases results in a substantial survival benefit only in younger patients with a low systemic tumor burden when compared to WBRT alone. It cannot be excluded that this effect is partially caused by the available salvage options after radiosurgery.Hintergrund und Ziel:Für Patienten mit inoperablen Hirnmetastasen ist die Ganzhirnbestrahlung (WBRT) seit Jahrzehnten die Standardtherapie. Die Radiochirurgie stellt eine effektive Therapiealternative dar, jedoch wurde bisher kein eindeutiger Überlebensvorteil nachgewiesen. Die Risikogruppen der rekursiven Partitionsanalyse (RPA) der RTOG ermöglichen einen sinnvollen, nicht randomisierten Vergleich von WBRT und Radiochirurgie.Patienten und Methodik:Von 1991 bis 1998 erhielten 117 nicht vorbehandelte Patienten mit ein bis drei Hirnmetastasen eine Linac-Radiochirurgie (mediane Dosis 20 Gy) ohne adjuvante WBRT. Zusätzlich wurden 26/117 Patienten (22%) wegen eines lokalen Metastasenrezidivs (4/117) oder neu aufgetretener Hirnmetastasen (24/117) erneut mittels Radiochirurgie, WBRT oder neurochirurgischer Resektion behandelt. Das Überleben dieser Patienten wurde mit einer historischen Gruppe verglichen (n = 138), die von 1978 bis 1991 bei ein bis drei Hirnmetastasen eine alleinige Ganzhirnbestrahlung (30–36 Gy/3-Gy-Fraktionen) erhielt. Hiervon wurden nur neun Patienten (7%) wegen eines Rezidivs erneut mit einer WBRT behandelt. Alle Patienten wurden entsprechend ihrem Alter, dem Allgemeinzustand (Karnofsky-Index) und der Präsenz extrakranieller Tumormanifestationen in die drei RPA-Klassen eingeteilt.Ergebnisse:In der RPA-Klasse I (Karnofsky-Index ≥ 70, Primärtumor kontrolliert, keine weiteren Metastasen, Alter < 65 Jahre) führte die Radiochirurgie zu einem medianen Überleben von 25,4 Monaten (n = 23, Konfidenzintervall [CI] 5,8–45,0) und war somit der WBRT signifikant überlegen (n = 9, 4,7 Monate, CI 3,8–5,5; p < 0,0001). In der RPA-Klasse III (Karnofsky-Index < 70) ließ sich kein signifikanter Vorteil der Radiochirurgie (n = 20, 4,2 Monate, CI 3,2–5,3) gegenüber der WBRT (n = 68, 2,5 Monate, CI 2,2–2,8) nachweisen. In der RPA-Risikoklasse II (alle anderen Patienten) führte die Radiochirurgie nur zu einem geringen, aber signifikanten Überlebensvorteil (Radiochirurgie: n = 74, 5,9 Monate, CI 3,2–8,5, WBRT: n = 61, 4,1 Monate, CI 3,4–4,9; p < 0,04).Schlussfolgerung:Im Vergleich zur alleinigen WBRT führt die Radiochirurgie bei Patienten mit ein bis drei Hirnmetastasen nur in jüngerem Alter und bei geringer systemischer Tumorausbreitung zu einer Prognoseverbesserung. Möglicherweise spielt hierfür die höhere Verfügbarkeit von Salvage-Therapien eine Rolle.

Linac Radiosurgery Versus Whole Brain Radiotherapy for Brain Metastases

Background and Purpose:For patients with inoperable brain metastases, whole brain radiotherapy (WBRT) has been the standard treatment for decades. Radiosurgery is an effective alternative strategy, but has failed to show a substantial survival benefit so far. The prognostic factors derived from the RTOG recursive partitioning analysis (RPA) provide a framework that allows a nonrandomized comparison of the two modalities.Patients and Methods:From 1991 to 1998, 117 patients with one to three previously untreated cerebral metastases underwent single-dose linac radiosurgery (median dose 20 Gy) without adjuvant WBRT. After radiosurgery, 26/117 patients (22%) had salvage WBRT, radiosurgery or neurosurgical resection of recurrent (4/117) and/or new (24/117) metastases. Survival of these patients was compared to a historical group of 138 patients with one to three lesions treated by WBRT (30–36 Gy/3-Gy fractions) from 1978 to 1991; only nine of these patients (7%) had salvage WBRT. All patients were classified into the three RPA prognostic classes based on age, performance score, and presence of extracranial tumor manifestations.Results:In RPA class I (Karnofsky performance score ≥ 70, primary tumor controlled, no other metastases, age < 65 years), radiosurgery resulted in a median survival of 25.4 months (n = 23, confidence interval [CI] 5.8–45.0) which was significantly longer than for WBRT (n = 9, 4.7 months, CI 3.8–5.5; p < 0.0001). In RPA class III (Karnofsky performance score < 70), no significant difference in survival between radiosurgery (n = 20, 4.2 months, CI 3.2–5.3) and WBRT (n = 68, 2.5 months, CI 2.2–2.8) was found. In RPA class II (all other patients), radiosurgery produced a small, but significant survival advantage (radiosurgery: n = 74, 5.9 months, CI 3.2–8.5, WBRT: n = 61, 4.1 months, CI 3.4–4.9; p < 0.04).Conclusion:Radiosurgery in patients with one to three cerebral metastases results in a substantial survival benefit only in younger patients with a low systemic tumor burden when compared to WBRT alone. It cannot be excluded that this effect is partially caused by the available salvage options after radiosurgery.Hintergrund und Ziel:Für Patienten mit inoperablen Hirnmetastasen ist die Ganzhirnbestrahlung (WBRT) seit Jahrzehnten die Standardtherapie. Die Radiochirurgie stellt eine effektive Therapiealternative dar, jedoch wurde bisher kein eindeutiger Überlebensvorteil nachgewiesen. Die Risikogruppen der rekursiven Partitionsanalyse (RPA) der RTOG ermöglichen einen sinnvollen, nicht randomisierten Vergleich von WBRT und Radiochirurgie.Patienten und Methodik:Von 1991 bis 1998 erhielten 117 nicht vorbehandelte Patienten mit ein bis drei Hirnmetastasen eine Linac-Radiochirurgie (mediane Dosis 20 Gy) ohne adjuvante WBRT. Zusätzlich wurden 26/117 Patienten (22%) wegen eines lokalen Metastasenrezidivs (4/117) oder neu aufgetretener Hirnmetastasen (24/117) erneut mittels Radiochirurgie, WBRT oder neurochirurgischer Resektion behandelt. Das Überleben dieser Patienten wurde mit einer historischen Gruppe verglichen (n = 138), die von 1978 bis 1991 bei ein bis drei Hirnmetastasen eine alleinige Ganzhirnbestrahlung (30–36 Gy/3-Gy-Fraktionen) erhielt. Hiervon wurden nur neun Patienten (7%) wegen eines Rezidivs erneut mit einer WBRT behandelt. Alle Patienten wurden entsprechend ihrem Alter, dem Allgemeinzustand (Karnofsky-Index) und der Präsenz extrakranieller Tumormanifestationen in die drei RPA-Klassen eingeteilt.Ergebnisse:In der RPA-Klasse I (Karnofsky-Index ≥ 70, Primärtumor kontrolliert, keine weiteren Metastasen, Alter < 65 Jahre) führte die Radiochirurgie zu einem medianen Überleben von 25,4 Monaten (n = 23, Konfidenzintervall [CI] 5,8–45,0) und war somit der WBRT signifikant überlegen (n = 9, 4,7 Monate, CI 3,8–5,5; p < 0,0001). In der RPA-Klasse III (Karnofsky-Index < 70) ließ sich kein signifikanter Vorteil der Radiochirurgie (n = 20, 4,2 Monate, CI 3,2–5,3) gegenüber der WBRT (n = 68, 2,5 Monate, CI 2,2–2,8) nachweisen. In der RPA-Risikoklasse II (alle anderen Patienten) führte die Radiochirurgie nur zu einem geringen, aber signifikanten Überlebensvorteil (Radiochirurgie: n = 74, 5,9 Monate, CI 3,2–8,5, WBRT: n = 61, 4,1 Monate, CI 3,4–4,9; p < 0,04).Schlussfolgerung:Im Vergleich zur alleinigen WBRT führt die Radiochirurgie bei Patienten mit ein bis drei Hirnmetastasen nur in jüngerem Alter und bei geringer systemischer Tumorausbreitung zu einer Prognoseverbesserung. Möglicherweise spielt hierfür die höhere Verfügbarkeit von Salvage-Therapien eine Rolle.

Linear accelerator radiosurgery for recurrent malignant tumors of the skull base

The efficacy of linear accelerator-based radiosurgery for patients who have preirradiated recurrent nasopharyngeal carcinomas and unresectable recurrent sarcomas invading the base of skull was assessed. Thirteen patients were treated: 8 patients had carcinomas arising from the nasopharynx (lymphoepithelioma, 4; squamous cell carcinoma, 2; adenoid-cystic, 2); 5 patients had sarcomas (rhabdomyosarcoma, 1; chordoma, 1; chondrosarcoma, 1; hemangiopericytoma, 2). All patients had had repeated tumor resections or irradiation, hindering any further conventional fractionated radiotherapy or surgery. Convergent-beam irradiation was performed with a modified linear accelerator (8-MeV photons). Because of irregular tumor configuration, multiple (up to seven) isocenters had to be used in 10 of 13 patients to match the target volume with the reference isodose (60%-80%). Each isocenter was irradiated with 6 to 10 arcs. The median planning target volume was 33 mL (4-128 mL) and the median dose was 15 Gy (9-24 Gy). Median survival time was 9 months in 8 patients who had recurrent nasopharyngeal carcinomas. Three patients who had complete or partial tumor remission survived 1.5 to 3.5 years. All of the sarcoma patients responded to radiosurgery. After a follow-up of 28 to 67 months, 4 of 5 patients are alive. This investigation demonstrates that radiosurgery is an effective tool in palliative treatment for patients who have recurrent, extensively pretreated nasopharyngeal cancer. Patients who have recurrent sarcomas of the base of skull may be treated for long-term palliation or even for cure.

Stereotactic iodine-125 brachytherapy for brain tumors: temporary versus permanent implantation

Stereotactic brachytherapy (SBT) has been described in several publications as an effective, minimal invasive and safe highly focal treatment option in selected patients with well circumscribed brain tumors <4 cm. However, a still ongoing discussion about indications and technique is hindering the definition of a clear legitimation of SBT in modern brain tumor treatment. These controversies encompass the question of how intense the irradiation should be delivered into the target volume (dose rate). For instance, reports about the use of high does rate (HDR) implantation schemes ( >40 cGy/h) in combination with adjuvant external beam radiation and/or chemotherapy for the treatment of malignant gliomas and metastases resulted in increased rates of radiation induced adverse tissue changes requiring surgical intervention. Vice versa, such effects have been only minimally observed in numerous studies applying low dose rate (LDR) regiments (3–8 cGy/h) for low grade gliomas, metastases and other rare indications. Besides these observations, there are, however, no data available directly comparing the long term incidences of tissue changes after HDR and LDR and there is, furthermore, no evidence regarding a difference between temporary or permanent LDR implantation schemes. Thus, recommendations for effective and safe implantation schemes have to be investigated and compared in future studies.