Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes.

Despite moderate improvements in outcome of glioblastoma after first-line treatment with chemoradiation recent clinical trials failed to improve the prognosis of recurrent glioblastoma. In the absence of a standard of care we aimed to investigate institutional treatment strategies to identify similarities and differences in the pattern of care for recurrent glioblastoma. We investigated re-treatment criteria and therapeutic pathways for recurrent glioblastoma of eight neuro-oncology centres in Switzerland having an established multidisciplinary tumour-board conference. Decision algorithms, differences and consensus were analysed using the objective consensus methodology. A total of 16 different treatment recommendations were identified based on combinations of eight different decision criteria. The set of criteria implemented as well as the set of treatments offered was different in each centre. For specific situations, up to 6 different treatment recommendations were provided by the eight centres. The only wide-range consensus identified was to offer best supportive care to unfit patients. A majority recommendation was identified for non-operable large early recurrence with unmethylated MGMT promoter status in the fit patients: here bevacizumab was offered. In fit patients with late recurrent non-operable MGMT promoter methylated glioblastoma temozolomide was recommended by most. No other majority recommendations were present. In the absence of strong evidence we identified few consensus recommendations in the treatment of recurrent glioblastoma. This contrasts the limited availability of single drugs and treatment modalities. Clinical situations of greatest heterogeneity may be suitable to be addressed in clinical trials and second opinion referrals are likely to yield diverging recommendations.

Radiosurgery/stereotactic radiotherapy in the therapeutical concept for skull base meningiomas.

OBJECTIVE: Microsurgical resection is still the treatment of choice for skull base meningiomas. But the risk of postoperative neurological deficits is high, and in many of these cases complete tumor removal cannot be achieved. Therefore recurrences are even more probable. Stereotactically guided radiation therapy - radiosurgery (RS) or stereotactic radiotherapy (SRT) - offers an additional or alternate treatment option for those patients. We evaluated local control rates, symptomatology, and toxicity. PATIENTS AND METHODS: 224 patients were treated with stereotactically guided radiation techniques in two departments between 1997 and 2003. 129 of 224 had recurrences after 1 to 3 prior tumor resections and 95 of 224 were treated with SRT/RS alone. 87.9% of cases had benign, 7.8% had atypical and 4.3% had malignant meningiomas. RS was only applied in 11 cases. Tumor volumes ranged from 0.16 ccm to 3.56 ccm. The other 213 patients had larger tumor volumes of up to 135 ccm or a meningioma close to optical structures. Therefore 183 cases were treated with SRT in normal fractions of 1.8-2 Gy in single doses up to 60 Gy. Hypofractionated SRT with single fraction doses of 5 or 4 Gy was applied in 30 cases. Follow-up data were available in 181 skull base meningiomas and the progression-free and overall survival rates, the toxicity and symptomatology were evaluated. RESULTS: The median follow-up was 36 months. The overall survival and the progression-free survival rates for 5 years were 92.9%, and 96.9%, respectively. Two tumor progressions have occurred to date but further follow up is required. Tumor volumes (TV) had shrunk about by 19.7% at 6 months (p<0.0001) and by 23.2% at 12 months (p<0.01) after SRT/RS. In 95.6% the symptoms had improved or were stable. Clinically significant acute toxicity (grade III) was seen in only 1 case (2.7%). Some patients developed late toxicity: 8.8% had grade I, 4.4% had grade II and 1.1% had grade III. No other neurological deficits occurred during follow-up. CONCLUSION: SRT and RS offer an additional or alternative treatment option with a high efficacy and few side effects for the tumor control of skull base meningiomas. An individual and interdisciplinary decision respecting treatment is needed for each patient. In cases of large TV (>4 ccm), tumors adjacent to critical structures (<2 mm) or in high-risk patients the use of SRT offers greater benefits.

Local irradiation prior to stem cell harvest has no influence on CD34+ yield: a quantitative analysis.

In patients with multiple myeloma, irradiation of bone marrow prior to mobilization of autologous peripheral blood progenitor cells (PBPCs) may lead to a reduced yield of CD34+ cells. Quantitative effects have not been sufficiently assessed. We retrospectively performed a multivariate analysis in 114 patients (67 men, 47 women) with multiple myeloma, of whom 53 (47%) patients had been irradiated prior to mobilization chemotherapy. High-dose cyclophosphamide followed by granulocyte colony-stimulating factor was used for mobilization in 84% of patients. In addition to previous chemotherapy, we quantitatively evaluated the dose and fractionation of prior irradiation, the volume of the irradiated bone marrow, and the time interval between radiation therapy and mobilization of PBPCs. The median volume of irradiated bone marrow was 9% (range 1-30%) of the estimated total hematopoietic bone marrow. The irradiated bone marrow volume and the number of CD34+ cells per kilogram of body weight in the first leukapheresis product showed no correlation. However, the time between irradiation and mobilization seemed to influence the yield of CD34+ cells. A comparison of irradiated patients with nonirradiated patients revealed no differences with respect to the CD34+ cell counts. We did not find a significant influence of the extent or the total dose of irradiation on the yield of CD34+ cells in the first leukapheresis product in patients with multiple myeloma. However, there may be an inverse correlation between the time elapsed since the last irradiation and the number of mobilized CD34+ cells.

[Analysis of factors affecting the prognosis of vertebral metastases]. / Faktorenanalyse zur Prognose vertebraler Metastasen.

The goal of this study was to evaluate factors for the prognosis of patients with metastatic spinal tumors. 139 patients with vertebral metastases were studied. The modified Tokuhashi Score (a preoperative score composed of six parameters) and single factors were analysed with statistical methods. The modified Tokuhashi Score showed a significant correlation (p = 0,0019) with survival time of patients. Additionally, only the Karnofsky Index as single parameter showed statistically significant correlation(p = 0.0016). Regarding the logistic regression, primary tumor, age, sex and Karnofsky Index were identified as prognostic factors for survival time. This trial could demonstrate that the Tokuhashi Score is a successful predicting tool for the assessment of prognosis of patients with vertebral metastases.

[Comparison of extracorporeal shockwave therapy (ESWT) with roentgen irradiation in supraspinatus tendon syndrome--a prospective randomized single-blind parallel group comparison]. / Vergleich der extrakorporalen Stosswellentherapie (ESWT) mit der Röntgenreizbestrahlung beim Supraspinatussehnensyndrom--Ein prospektiver randomisierter einfachblinder Parallelgruppenvergleich.

AIM: Extracorporal shock wave therapy (FSWT) is applied in the case of supraspinatus tendinitis if conservative therapies have failed. So far there has been no controlled study comparing the effectiveness of ESWT with an established conservative method of therapy such as X-ray stimulation radiotherapy. METHOD: Thirty patients with chronic supraspinatus tendinitis were admitted into the prospective randomised study. After randomisation, the patients were treated either three times with 2000 pulses (energy flux density ED+ 0.33 mJ/mm2) with a Storz Minilith SL1 after one week, or with X-ray stimulation radiotherapy with 6 x 0.5 Gy on the ICRU reference point (1 neutral fraction/day) with cobalt 60 gamma rays. Primary endpoint was the age-corrected constant score. RESULTS: In the ESWT group the average age-corrected constant score rose from 50.1 points before ESWT to 91.5 points after 12 weeks and to 97.8 after 52 weeks. In the radiotherapy group it improved from 47.6 through 79.5 points to 87.4 points. CONCLUSION: No statistically significant differences were proven between ESWT and radiotherapy. ESWT appears to be at least equivalent to radiotherapy in treating chronic supraspinatus tendinitis syndrome and can avoid a dose of radiation for patients and staff. A comprehensive randomised study is, however necessary to ensure the equivalence of ESWT.

Acute toxicity and changes in quality of life during a combined radio-chemotherapy of glioblastomas with topotecan (Hycamtin).

BACKGROUND: Because of the pronounced radioresistance of glioblastoma multiforme the prognosis of this disease remains poor. Therefore, we investigated the impact of an additional simultaneous chemotherapy with the topoisomerase-I inhibitor topotecan (Hycamtin) on the quality of life and toxicity of radiotherapy. PATIENTS AND METHODS: In this multicenter trial patients with histologically proven glioblastoma multiforme underwent a simultaneous radio-chemotherapy. Including pilot phase 60 patients, 41 male and 19 female, were treated. Age ranged from 26 to 76 years, the mean was 57 years. Conventional fractionated conformal radiotherapy was performed with daily doses of 2.0 Gy to a total dose of 60 Gy. 1 hour prior to irradiation 0.5 mg (absolute dose) of topotecan were administered intravenously resulting in a cumulative dose of 15 mg. Besides hematologic and non-hematologic toxicity, quality of life was assessed by Karnofsky index and Spitzer index. Additionally local control and survival time were recorded. RESULTS: 57 patients completed the combined therapy. Median administered dose of radiation was 60 Gy (16-76 Gy). Median cumulative topotecan dose was 15 mg (7.5-18.5 mg). Grade-III toxicity was found in six cases (two hematologic, two motoric disorder, one infection, one nausea) and grade-IV toxicity in three cases (one esophagitis, one motoric disorder, one mental disorder). Two patients died of septic disease most likely caused by steroid induced immunosuppression. Mean Karnofsky index and Spitzer index initially, at the end of therapy and 6 weeks after therapy showed values of 87%, 81% and 80% and 19 points, 18 points and 19 points, respectively. Median survival time was 15 months. CONCLUSION: This multimodal approach for patients with glioblastoma multiforme is well tolerated. Quality of life remains preserved and outpatient treatment is possible. The relatively long median survival time even for patients bearing macroscopic tumors is promising.

Aberrant p21 regulation in radioresistant primary glioblastoma multiforme cells bearing wild-type p53.

OBJECT: A clearer understanding of the cellular mechanisms involved in the response to ionizing radiation is pivotal to the development of new therapeutic strategies for glioblastoma multiforme (GBM). To gain insight into dynamic functional aspects of cell cycle regulation and the control of apoptosis in GBMs, the authors investigated the molecular changes induced by ionizing radiation in genetically characterized primary GBMs in vitro compared with secondary GBMs, Grades II and III gliomas, and three GBM cell lines. METHODS: Irradiation of primary GBMs bearing wild-type (wt) p53 invariably fails to invoke the G, checkpoint and apoptosis in vitro. In approximately half of these primary GBMs a defect lies at or above the level of p53 because transcriptional activation of p21 and bax after irradiation does not occur. The failure of a p21 response to irradiation is invariably accompanied by overexpression of p21 mRNA under nonirradiated conditions. In all remaining primary GBMs transcriptional activation of p21 after irradiation does occur, suggesting that a defect downstream from p21 prevents G, arrest. CONCLUSIONS: These results show that the G, checkpoint and the p53 pathway are dysfunctional in primary GBMs in vitro, despite the presence of an intact p53 gene. The data also suggest that primary GBMs may be divided into two categories on the basis of their p21 response to irradiation.

First experience with I-123-alpha-methyl-tyrosine spect in the 3-D radiation treatment planning of brain gliomas.

PURPOSE: This study compares the results of iodine-123-alpha-methyl-tyrosine single photon computed emission tomography (IMT-SPECT) with magnetic resonance imaging (MRI) in tumor volume definition of brain gliomas. Furthermore, it evaluates the influences of the information provided from IMT-SPECT for three-dimensional (3D) conformal treatment planning. METHODS AND MATERIALS: In 30 patients with nonresected, histologically proven brain gliomas (glioblastoma-13 patients, astrocytoma Grade III-12 patients, astrocytoma Grade II-3 patients, oligodendroglioma Grade III-1 patient, oligodendroglioma Grade II-1 patient), IMT-SPECT and MRI were performed pretherapeutically in the same week. A special software system allowed the coregistration of the IMT-SPECT and MRI data. The gross tumor volume (GTV) defined on the IMT-SPECT/T2-MRI fusion images (GTV-IMT/T2) was compared with the GTV-T2, defined on the T2-MRI alone. On the IMT-SPECT/T1Gd-MRI overlays, the volume of the IMT tumor uptake (GTV-IMT) was compared with the volume of the gadolinium (Gd) enhancement (GTV-T1Gd). The initial planning target volume (PTV) and the boost volume (BV) outlined on the IMT-SPECT/T2-MRI co-images were analyzed comparatively to the PTV and BV delineated using the T2-MRI alone. RESULTS: In all 30 patients a higher IMT uptake of tumor areas, compared to the normal brain tissue was observed. Mean GTV-IMT, mean GTV-T2, and mean GTV-T1Gd were 43, 82, and 16 cm(3), respectively. IMT tumor uptake outside the contrast enhancement regions was observed in all patients. Mean relative increase of tumor volume defined on the fusion images, GTV-IMT/T1Gd versus GTV-T1Gd alone was 78%. IMT tumor uptake areas outside the GTV-T2 were registered in 7 patients (23%). In these patients, the mean increase GTV-IMT/T2 was 33% higher than GTV-T2, defined according to the T2-MRI data alone. The additional information provided by IMT-SPECT modified minimally the initial PTV (mean relative increase PTV-IMT/T2 versus PTV-T2, 5%) but significantly the BV (mean relative increase BV-IMT/T2 versus BV-T2, 37%). CONCLUSION: In a significant number of patients, the IMT-SPECT investigation improves tumor detection and delineation in the planning process. This has important consequences in the 3D conformal treatment planning, especially in the delineation of BV and in dose escalation studies.

The value of F-18-fluorodeoxyglucose PET for the 3-D radiation treatment planning of malignant gliomas.

PURPOSE: The aim of the study was to determine the impact of positron emission tomography using the glucose analogue fluorine-18-fluorodeoxyglucose (FDG-PET) on the delineation of the target volume in three-dimensional radiation treatment planning of primary brain tumors. METHODS AND MATERIALS: In 18 patients with histologically proven (8x biopsy, 10x subtotal resection) primary brain tumors (8 astrocytomas grade III, one mixed glioma grade III, and 9 glioblastomas), magnetic resonance imaging (MRI) with gadolinium-DTPA and FDG-PET were performed in radiation treatment position within the same week. A computer program was developed for fusion of the PET and MR images. On corresponding axial slices, FDG uptake was compared to contrast enhancement in T1-weighted and to signal hyperintensity in T2-weighted MR images. Based on PET and MRI data, three-dimensional treatment planning was performed. All patients underwent linear accelerator (LINAC) radiotherapy. RESULTS: In MRI, all tumors and the surrounding edema were visible as hyperintense lesions in the T2-weighted images. 17/18 tumors showed contrast enhancement. In FDG-PET, 16 tumors showed hypermetabolism compared to normal white matter, whereas only 8/18 tumors showed hypermetabolism compared to normal gray matter. White matter edema was associated with decreased FDG uptake in all patients. The area of increased FDG uptake correlated closely with contrast enhancement, only in one case the volume of increased FDG uptake was larger than the area of contrast enhancement. Mean tumor volumes obtained by MRI T1 + Gd, T2, and PET were 30, 106, and 10 ml, respectively. Survival was comparable to data in the literature with a 1-year survival of 39% and a median survival of 310 days. CONCLUSION: Only in a minority of patients did FDG-PET provide additional information for radiation treatment planning. This is mainly caused by the high intensity of FDG uptake in normal brain tissue. PET may be of greater value in the definition of regions that should obtain a radiation dose boost.

[3-Dimensional irradiation planning in brain tumors. The advantages of the method and the clinical results]. / Dreidimensionale Bestrahlungsplanung bei Hirntumoren. Vorteile der Methode und klinische Ergebnisse.

PURPOSE: Radiotherapy became an important component in the treatment of brain gliomas. The aim of this study is to analyse several advantages of the three-dimensional conformal radiation therapy in comparison with a two-dimensional conventional technique and to present the clinical results of 43 patients with brain gliomas treated according to a three-dimensional planning. PATIENTS AND METHOD: Between January 1994 and December 1995, 43 patients with malignant brain gliomas (WHO III and IV) were treated in our department according to a three-dimensional treatment planning. The patients received a total irradiation dose of 60 Gy, 2 Gy/day, 5 days/week. The rate of survival was analysed in relation with the known prognostical factors: histology, Karnofsky index, age, resection status. In 10 patients a three-dimensional treatment planning was compared with a conventional two-dimensional planning: the volume of the normal brain tissue irradiated to high dose levels (95% isodose) and the normal tissue complication probability (NTCP) for the brain by Kutcher and Lyman were comparatively analysed. RESULTS: The survival rate for the whole group was 14 months. The histology of the tumor, age, Karnofsky index and resection status were important prognostical factors. The three-dimensional planning allows a 15 to 20% reduction in the volume of normal brain tissue irradiated to high dose levels (95% isodose). The NTCP is significantly lower using the three-dimensional technique (range 0.03% to 13%), in comparison with the two-dimensional conventional technique (range 0.1% to 26%). The value of NTCP increases with tumor volume. CONCLUSIONS: Concerning the tumor control and survival rate, the three-dimensional treatment planning shows no advantages compared to the standard conventional methods. The main advantage of the three-dimensional treatment planning is the possibility to spare normal brain tissue. The possibility to integrate mathematical models in the evaluation of the therapy could give this technique new dimensions.

Direct bonding to Adlloy-treated amalgam.

The purpose of this study was to test the bond-enhancing effect by modifying amalgam surfaces with Adlloy (a gallium-tin liquid alloy) and bonding brackets by using two different resin systems. Bond strength and location of bond failure was assessed by using (1) Concise (3M Dental Products) and (2) C&B Metabond (Parkell) systems with and without the use of Adlloy alloy. Class V buccal amalgam restorations (n = 132) were subjected to one of two surface treatments: (1) sandblasting or (2) sandblasting plus Adlloy treatment. Mandibular premolar brackets were bonded with Concise composite resin or C&B Metabond (adhesive) to amalgam surfaces. All specimens were stored in 37 degrees C water for 10 weeks and subjected to thermocycling before bond strength testing. The laboratory shear bond strength of Concise material to amalgam was not improved after Adlloy modification. However, Adlloy-treated amalgam significantly increased the laboratory shear bond strength of orthodontic brackets bonded with C&B Metabond material. The majority (58%) of the bond failures of C&B Metabond bonded to non-Adlloy treated-amalgam occurred at the amalgam-adhesive interface, whereas the majority (58%) of the bond failure of C&B Metabond bonded to Adlloy-treated amalgam failed within the adhesive. Fracture within the amalgam during debonding was observed with C&B Metabond bonded to sandblasted amalgam (21%) and Adlloy-treated amalgam (15%). Regardless of Adlloy treatment, C&B Metabond would appear to provide adequate orthodontic bonding to amalgam; however, there may exist a potential risk of amalgam restoration fracture upon debonding.

Fluorine-18-FDG PET and iodine-123-IMT SPECT in the evaluation of brain tumors.

UNLABELLED: The high glucose utilization of normal gray matter limits the detection of brain tumor tissue by PET using 18F-fluorodeoxyglucose (FDG). The aim of this study was to evaluate whether the examination of amino acid transport with the SPECT tracer 123l-alpha-methyl-L-tyrosine (IMT) allows better identification of tumor tissue than FDG-PET. METHODS: Nineteen patients (16 with gliomas, 3 with nontumorous lesions) were included in the study. Two independent observers classified PET and SPECT images as positive or negative for tumor tissue and defined the extent of tumor with regions of interest. Tracer uptake of FDG and IMT was quantified by calculating the tumor uptake relative to contralateral gray and white matter. RESULTS: SPECT studies were interpreted concordantly in 18 patients (kappa = 0.77) and all tumors were identified by both observers. PET studies were interpreted discordantly in 4 patients (kappa = 0.52) and only 10 tumors were identified by both observers, interobserver variability in definition of tumor extent was significantly lower in the IMT-SPECT than in the FDG-PET studies (p = 0.03). Mean tumor uptake relative to gray and white matter was 1.93 +/- 0.42 and 2.25 +/- 0.46 for IMT and 0.93 +/- 0.32 and 1.61 +/- 0.52 for FDG. All tumor uptake ratios were significantly (p < 0.01) higher for IMT than FDG, even when only glioblastomas were analyzed. No significant correlation was observed between the various uptake ratios of FDG and IMT. CONCLUSION: Despite the lower resolution and lower sensitivity of SPECT compared with PET, IMT-SPECT was clearly superior to FDG-PET in the detection and delineation of tumor tissue.

Calibration of misonidazole labeling by simultaneous measurement of oxygen tension and labeling density in multicellular spheroids.

To correlate misonidazole concentrations and oxygen pressures (Po2) at identical locations within EMT6/Ro multi-cell spheroids (mean diameters +/- SD: 867 +/- 20 microns), Po2 measurements were performed with oxygen-sensitive microelectrodes during incubation of these spheroids with tritiated misonidazole (10 mg/I; 445 microCi/mg). In each individual spheroid, Po2 profiles were correlated with the corresponding spatial distribution of misonidazole as quantified by conventional autoradiography and grain counting. To compare the oxygenation status of spheroids in the measuring chamber with that of spheroids in spinner culture, misonidazole labeling was performed in both environments following the same protocol. All experiments were conducted in 20% oxygen and BME or in 5% oxygen and DMEM to obtain spheroids with different degrees of oxygenation. Labeled misonidazole was fairly evenly distributed in the outer, better oxygenated regions of EMT6 spheroids. In contrast, there was an accumulation of the labeled substance near central necrosis where low oxygen tensions were measured. Grain densities were similar at corresponding oxygen pressures under both environmental conditions. Except for some scatter, grain density as a function of oxygen pressure showed little variation in the Po2 range of 20-60 mm Hg, but exhibited a steep increase below 10 mm Hg. The findings imply that a substantial rise in local misonidazole labeling indicates a metabolically active tissue region at low Po2 that is not necessarily identical with the radiobiologically hypoxic cell fraction. A comparison of the labeling densities of spheroids in spinner flasks and in the Po2 measuring chamber indicates that oxygenation of spheroids is better in rotation culture than during microelectrode measurements.