Klaus Haselsberger

Gamma knife for glioma: Selection factors and survival

PURPOSE To determine factors associated with survival differences in patients treated with radiosurgery for glioma. METHODS AND MATERIALS We analyzed 189 patients treated with Gamma Knife radiosurgery for primary or recurrent glioma World Health Organization (WHO) Grades 1-4. RESULTS CONCLUSION The median minimum tumor dose was 16 Gy (8-30 Gy) and the median tumor volume was 5.9 cc (1.3-52 cc). Brachytherapy selection criteria were satisfied in 65% of patients. Median follow-up of all surviving patients was 65 weeks after radiosurgery. For primary glioblastoma patients, median survival from the date of pathologic diagnosis was 86 weeks if brachytherapy criteria were satisfied and 40 weeks if they were not (p = 0.01), indicating that selection factors strongly influence survival. Multivariate analysis showed that increased survival was associated with five variables: lower pathologic grade, younger age, increased Karnofsky performance status (KPS), smaller tumor volume, and unifocal tumor. Survival was not found to be significantly related to radiosurgical technical parameters (dose, number of isocenters, prescription isodose percent, inhomogeneity) or extent of preradiosurgery surgery. We developed a hazard ratio model that is independent of the technical details of radiosurgery and applied it to reported radiosurgery and brachytherapy series, demonstrating a significant correlation between survival and hazard ratio. CONCLUSIONS Survival after radiosurgery for glioma is strongly related to five selection variables. Much of the variation in survival reported in previous series can be attributed to differences in distributions of these variables. These variables should be considered in selecting patients for radiosurgery and in the design of future studies.

Combined endoscopic surgery and radiosurgery as treatment modality for olfactory neuroblastoma (esthesioneuroblastoma).

SummaryObject. Treatment of esthesioneuroblastoma (olfactory neuroblastoma) has been considerably improved by microsurgical techniques. Nevertheless, these rare tumours of the frontal skull base are still associated with high rates of tumour recurrence and mortality, thus remaining a challenge even for experienced surgeons. A novel therapeutic approach that combines endoscopic sinus surgery and Gamma Knife radiosurgery is presented here. Taking into account the rarity of the disease the present study comprises a relatively large series of patients treated in a similar manner.Methods. 14 patients (8 males, 6 females) aged 27–75 years (median 38) were treated between May 1993 and December 2003. This series comprises 12 newly diagnosed esthesioneuroblastomas. Two more patients had already previously undergone surgery (24/39 months earlier). Paranasal and nasal endoscopic sinus surgery was performed. Marginal irradiation doses ranging from 15–34 Gy were given to the residual tumours by means of radiosurgery (Gamma Knife) involving 1–7 isocentres within 3 months after surgery. Median follow-up is 58 months (range 13–128).Results. There was no mortality. In all patients tumour control was achieved within the treated area. 4 patients underwent a second radiosurgical procedure 6–79 months (median 34 months) after initial radiosurgery. One patients had to undergo an additional craniotomy because of extensive neoplastic infiltration, 1 developed postoperative liquorrhea, 1 case was complicated by bilateral frontal sinusitis. All patients complained of nasal discharge and crusts. Karnovsky Index – preoperatively ranging from 80%–100% – remained stable in 12 patients, an improvement was observed in 2 cases.Conclusions. Based on the favourable results recorded so far, the combination of endoscopic sinus surgery and radiosurgery can be considered a promising treatment option for esthesioneuroblastoma that merits further consideration.

Tissue uptake of BSH in patients with glioblastoma in the EORTC 11961 phase I BNCT trial.

Purpose: The uptake of the boron compound Na2B12H10-SH (BSH) in tumor and normal tissues was investigated in the frame of the EORTC phase I trial ‘Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility’ (protocol 11961).Methods and Materials: The boron concentration in blood, tumor, normal brain, dura, muscle, skin and bone was detected using inductively coupled plasma-atomic emission spectroscopy in 13 evaluable patients. In a first group of 10 patients 100 mg BSH/kg bodyweight (BW) were administered; a second group of 3 patients received 22.9 mg BSH/kg BW. The toxicity due to BSH was evaluated.Results: The average boron concentration in the tumor was 19.9±9.1 ppm (1 standard deviation (SD)) in the high dose group and 9.8±3.3 ppm in the low dose group, the tumor/blood ratios were 0.6±0.2 and 0.9±0.2, respectively. The highest boron uptake has been detected in the dura, very low uptake was found in the bone, the cerebro-spinal fluid and especially in the brain (brain/blood ratio 0.2±0.02 and 0.4±0.2). No toxicity was detected except flush-like symptoms in 2 cases during a BSH infusion at a much higher speed than prescribed.Conclusion: BSH proved to be safe for clinical application at a dose of 100 mg BSH/kg infused and at a dose rate of 1 mg/kg/min. The study underlines the importance of a further investigation of BSH uptake in order to obtain enough data for significant statistical analysis. The boron concentration in blood seems to be a quite reliable parameter to predict the boron concentration in other tissues.

Surgery of tumours of the lateral ventricle

SummaryTumours of the lateral ventricle in most cases enlarge significantly before signs and symptoms are exhibited.In the years between 1980 and 1991 we encountered 55 patients of all age groups with tumours of the lateral ventricle. All were diagnosed either by CT or MRI, and in lesions with good enhancement on CT additional angiography was performed. All 55 tumours were operated upon using microsurgical techniques. The approach was chosen according to the location of the tumour, preferably transcortical. In selected cases large tumours were removed in a twostage operation. Only in one frontal horn and Cella media tumour an interhemispheric transcallosal approach was used. Postoperative or surgically related mortality was experienced in 3 cases. Life expectancy and morbidity were dependent upon histology.

Pharmacokinetics of Na2B12H11SH (BSH) in patients with malignant brain tumours as prerequisite for a phase I clinical trial of boron neutron capture

SummaryThe disposition of Na2B12H11SH (BSH) in patients with malignant glioma has been investigated, in preparation for a Phase I clinical trial of boron neutron capture therapy. BSH was found to possess a linear disposition over the dosage interval investigated (up to 75 mg/kg). A bi-phasic blood pharmacokinetics was observed. Tumour-to-blood ratios showed variations between patients between 0.08 and 5.1. The data allow the definition of amount of BSH and timing of infusion for a Phase I clinical trial protocol.

Radiosurgery of Vestibular Schwannomas: A Minimally Invasive Alternative to Microsurgery

Summary¶ From April 1992 till December 1998 stereotactic radiosurgery (Gamma Knife) was applied to 192 patients with vestibular schwannomas. 56 of them had radiosurgery as primary treatment modality and were followed-up for at least 4 years (48–80 months, median 62). Without fatal complications, control of tumour growth was achieved in all but three cases, useful hearing being preserved in more than one half of the patients (62%). The neurological state improved in 30 patients (54%). Irradiation-associated adverse effects (18%) comprised neurological signs (incomplete facial palsy, four cases (two recovered completely), and mild trigeminal neuropathy, three cases, respectively) and morphological changes (three patients) marked by an enlargement of pre-existing cystic components calling for additional surgical treatment: Microsurgical decompression was performed in two cases, the third patient underwent a shunting procedure because of hydrocephalus formation. Based on the present data, radiosurgery represents an effective treatment for vestibular schwannomas associated with an exceptionally low mortality rate and a good quality of life. With respect to the preservation of cranial nerve function, results are comparable to microsurgical resection. A short duration of hospitalization and a quick return to normal activities constitute further advantages and contribute to cost effectiveness in public health care.

Optimal timing of neutron irradiation for boron neutron capture therapy after intravenous infusion of sodium borocaptate in patients with glioblastoma

PURPOSE A cooperative study in Europe and Japan was conducted to determine the pharmacokinetics and boron uptake of sodium borocaptate (BSH: Na(2)B(12)H(11)SH), which has been introduced clinically as a boron carrier for boron neutron capture therapy in patients with glioblastoma. METHODS AND MATERIALS Data from 56 patients with glioblastoma who received BSH intravenous infusion were retrospectively reviewed. The pharmacokinetics were evaluated in 50 patients, and boron uptake was investigated in 47 patients. Patients received BSH doses between 12 and 100 mg/kg of body weight. For the evaluation, the infused boron dose was scaled linearly to 100 mg/kg BSH. RESULTS In BSH pharmacokinetics, the average value for total body clearance, distribution volume of steady state, and mean residence time was 3.6 +/- 1.5 L/h, 223.3 +/- 160.7 L, and 68.0 +/- 52.5 h, respectively. The average values of the boron concentration in tumor adjusted to 100 mg/kg BSH, the boron concentration in blood adjusted to 100 mg/kg BSH, and the tumor/blood boron concentration ratio were 37.1 +/- 35.8 ppm, 35.2 +/- 41.8 ppm, and 1.53 +/- 1.43, respectively. A good correlation was found between the logarithmic value of T(adj) and the interval from BSH infusion to tumor tissue sampling. About 12-19 h after infusion, the actual values for T(adj) and tumor/blood boron concentration ratio were 46.2 +/- 36.0 ppm and 1.70 +/- 1.06, respectively. The dose ratio between tumor and healthy tissue peaked in the same interval. CONCLUSION For boron neutron capture therapy using BSH administered by intravenous infusion, this work confirms that neutron irradiation is optimal around 12-19 h after the infusion is started.

Postoperative treatment of glioblastoma with BNCT at the Petten Irradiation Facility (EORTC Protocol 11961)

SummaryThe boron neutron capture therapy is based on the reaction occuring between the isotope10B and thermal neutrons. A low energy neutron is captured by the nucleus and it disintegrates into two densly ionising particles, Li nucleus and He nucleus (α particle), with high biological effectiveness. On the basis of comprehensive preclinical investigations in the frame of the European Collaboration with Na2B12H11SH (BSH), as boron delivery agent, the first European phase I, clinical trial was designed at the only available epithermal beam in Europe, at the High Flux Reactor, Petten, in the Netherland. The goal of this study is to establish the safe BNCT dose for cranial tumors under defined conditions.BNCT is applied as postoperative radiotherapy in 4 fractions, after removal of the tumor for a group of patients suffering from glioblastoma, who would have no benefit from conventional treatment, but have sufficient life expectancy to detect late radiation morbidity due to BNCT.The starting dose is set at 80% of the dose where neurological effects occured in preclinical large animal experiments following a single fraction. The radiation dose will be escalated, by constant boron concentration in blood, in 4 steps for cohorts of ten patients, after an observation period of at least 6 months after the end of BNCT of the last patient of a cohort.The adverse events on healthy tissues due to BSH and due to the radiotherapy will be analysed in order to establish the maximal tolerated dose and dose limiting toxicity. Besides of the primary aim of this study the survival will be recorded. The first patient was treated in October 1997, and further four patients have been irradiated todate. The protocol design proved to be well applicable, establishing the basis for scientific evaluation, for performance of safe patient treatment in a very complex situation and for opening the possibility to perform further clinical research work on BNCT.

Staged gamma knife radiosurgery for large critically located benign meningiomas: evaluation of a series comprising 20 patients

Objectives: This study investigated the efficacy of staged radiosurgical treatment for intracranial meningiomas exceeding 3 cm in diameter. Methods: Between April 1992 and May 2008, staged gamma knife radiosurgery was performed in 20 patients with large benign meningiomas. 14 patients had undergone surgery at least once. The patients’ ages ranged between 26 and 73 years (median 60.5). Tumour volumes measured between 13.6 and 79.8 cm3 (median 33.3) and treatment volumes between 5.4 and 42.9 cm3 (median 19.0). Of 41 treatments, the prescription dose at the tumour margin was 12 Gy for 33 treatments, 10 Gy for one treatment, 14 Gy for four treatments, 15 Gy for one treatment and 25 Gy for a further two treatments (median 12 Gy to a marginal isodose of 45%). Median follow-up was 7.5 years. Results: Tumour control was achieved in 90% of our series (25% tumour regression, 65% stable size). Two patients (10%) experienced tumour progression outlying the planning target volumes treated by an additional radiosurgical procedure. Thereafter tumour volume decreased in one patient and remained stable in the second one. Clinically, nine patients (45%) improved within the time of follow-up and 11 (55%) remained unchanged. Conclusion: As a result of excellent tumour control at a low concomitant morbidity, staged radiosurgical treatment for meningiomas represents a safe treatment modality that can be recommended for meningiomas in critical locations either after incomplete surgery or as primary treatment for patients with significant comorbidity.

Effect of intravenous mannitol on cat pial arteries and veins during normal and elevated intracranial pressure.

In two series of cats, totaling 12 animals, the effect of 1 g of intravenous mannitol per kg over 15 minutes on pial vessels (cranial window technique, multichannel videoangiometry) and intracranial pressure (ICP) was investigated under circumstances of normal ICP and ICP elevated to 20 mm Hg by the cisternal infusion of mock cerebrospinal fluid. Under conditions of normal ICP, mannitol induced an 18% reduction of ICP at the end of the infusion and a further decrease to 38% below the initial level 10 minutes later. Pial veins and arteries remained more or less unreactive over 35 minutes, with changes never exceeding 2 to 3%. Administration of mannitol during elevated ICP (20 mm Hg) reduced ICP by 15% during the administration period; during the subsequent 15 minutes, ICP returned to pretreatment levels. Pial arteries remained unreactive during mannitol infusion; however, they started to dilate during the subsequent 15 minutes to +8%. Venous calibers showed no noticeable changes. It is concluded that mannitol in clinically relevant doses does not exert a significant constrictive effect on cerebral arteries and veins and that mannitol acts on ICP probably via an osmotic effect rather than by a direct effect on cerebral blood volume.