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This article presents the rare case of a 54-year-old gentleman with primary glioblastoma developing multiple extracranial metastases 7 months after diagnosis. Initially, the patient complained of progressive headaches, confusion, and weakness of the left arm. Magnetic resonance imaging of the brain showed a right temporoparietal tumor with substantial surrounding subcortical edema and midline shift to the left. Two consecutive craniotomies resulted in complete microsurgical resection of the lesion. Histology was consistent with a World Health Organization grade IV, IDH-wildtype glioblastoma. Further treatment was standard chemoradiation including intensity-modulated radiotherapy with oral temozolomide chemotherapy. Seven months after diagnosis, the cranial lesion progressed, and the patient developed painful metastases in multiple bones and suspicious right-sided cervical lymph nodes. Immunohistochemistry and molecular signature supported the case of a metastatic glioblastoma. Further treatment was palliative radiotherapy of the spinal lesions along with symptomatic pain management. Extracranial metastasis of glioblastoma is a rare complication of which only a few cases have been reported in the literature. Little is known about the precise mechanisms of tumor dissemination and the appropriate treatment., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: Sarcopenia may complicate treatment in cancer patients. Herein, we assessed whether sarcopenia measurements derived from radiation planning computed tomography (CT) were associated with complications and tumor progression during radiochemotherapy for glioblastoma., Methods: Consecutive patients undergoing radiotherapy planning for glioblastoma between 2010 and 2021 were analyzed. Retrocervical muscle cross-sectional area (CSA) was measured via threshold-based semi-automated radiation planning CT analysis. Patients in the lowest sex-specific quartile of muscle measurements were defined as sarcopenic. We abstracted treatment characteristics and tumor progression from the medical records and performed uni- and multivariable time-to-event analyses., Results: We included 363 patients in our cohort (41.6% female, median age 63 years, median time to progression 7.7 months). Sarcopenic patients were less likely to receive chemotherapy (p < 0.001) and more likely to be treated with hypofractionated radiotherapy (p = 0.005). Despite abbreviated treatment, they more often discontinued radiotherapy (p = 0.023) and were more frequently prescribed corticosteroids (p = 0.014). After treatment, they were more often transferred to inpatient palliative care treatment (p = 0.035). Finally, progression-free survival was substantially shorter in sarcopenic patients in univariable (median 5.1 vs. 8.4 months, p < 0.001) and multivariable modeling (hazard ratio 0.61 [confidence interval 0.46-0.81], p = 0.001)., Conclusion: Sarcopenia is a strong risk factor for treatment discontinuation and reduced progression-free survival in glioblastoma patients. We propose that sarcopenic patients should receive intensified supportive care during radiotherapy and during follow-up as well as expedited access to palliative care., (© 2024. The Author(s).)

Purpose: No standard treatment has yet been established for recurrent glioblastoma (GBM). In this context, the aim of the current study was to evaluate safety and efficacy of reirradiation (re-RT) by radiosurgery or fractionated stereotactic radiotherapy (SRS/FSRT) in association with regorafenib., Methods: Patients with a histological or radiological diagnosis of recurrent GBM who received re-RT by SRS/FSRT and regorafenib as second-line systemic therapy were included in the analysis., Results: From January 2020 to December 2022, 21 patients were evaluated. The median time between primary/adjuvant RT and disease recurrence was 8 months (range 5-20). Median re-RT dose was 24 Gy (range 18-36 Gy) for a median number of 5 fractions (range 1-6). Median regorafenib treatment duration was 12 weeks (range 3-26). Re-RT was administered before starting regorafenib or in the week off regorafenib during the course of chemotherapy. The median and the 6‑month overall survival (OS) from recurrence were 8.4 months (95% confidence interval [CI] 6.9-12.7 months) and 75% (95% CI 50.9-89.1%), respectively. The median progression-free survival (PFS) from recurrence was 6 months (95% CI 3.7-8.5 months). The most frequent side effects were asthenia that occurred in 10 patients (8 cases of grade 2 and 2 cases of grade 3), and hand-foot skin reaction (2 patients grade 3, 3 patients grade 2). Adverse events led to permanent regorafenib discontinuation in 2 cases, while in 5/21 cases (23.8%), a dose reduction was administered. One patient experienced dehiscence of the surgical wound after reintervention and during regorafenib treatment, while another patient reported intestinal perforation that required hospitalization., Conclusion: For recurrent GBM, re-RT with SRT/FSRT plus regorafenib is a safe treatment. Prospective trials are necessary., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Background: Glioblastoma is the most common malignant brain tumor in human adults. Despite several improvements in resective as well as adjuvant therapy over the last decades, its overall prognosis remains poor. As a means of improving patient outcome, the possibility of enhancing radiation response by using radiosensitizing agents has been tested in an array of studies., Methods: A comprehensive review of clinical trials involving radiation therapy in combination with radiosensitizing agents on patients diagnosed with glioblastoma was performed in the National Center for Biotechnology Information's PubMed database., Results: A total of 96 papers addressing this matter were published between 1976 and 2021, of which 63 matched the subject of this paper. All papers were reviewed, and their findings discussed in the context of their underlining mechanisms of radiosensitization., Conclusion: In the history of glioblastoma treatment, several approaches of optimizing radiation-effectiveness using radiosensitizers have been made. Even though several different strategies and agents have been explored, clear evidence of improved patient outcome is still missing. Tissue-selectiveness and penetration of the blood-brain barrier seem to be major roadblocks; nevertheless, modern strategies try to circumvent these obstacles, using novel sensitizers based on preclinical data or alternative ways of delivery., (© 2022. The Author(s).)

Purpose: Purpose of this study was to investigate overall survival in recurrent glioblastoma treated with either carbon ion reirradiation or photon reirradiation., Materials and Methods: In this retrospective study we evaluated 78 consecutive patients with recurrent IDH (Isocitrate dehydrogenase)-wildtype glioblastoma (38 patients carbon ion re-radiotherapy, 40 patients photon re-radiotherapy) treated with either carbon ion reirradiation or stereotactic photon reirradiation. 45 Gy (RBE; 15 fractions) carbon ion reirradiation (CIRT) or 39 Gy (13 fractions) photon reirradiation (FSRT) was administered, respectively. Overall survival was investigated with respect to histological, clinical, and epidemiological features. Kaplan-Meier and multivariate Cox statistics were calculated. A propensity score-matched analysis of the FSRT and CIRT groups using variables from a validated prognosis score was carried out., Results: The type of reirradiation (CIRT vs. FSRT) significantly influenced overall survival-8.0 months vs. 6.5 months (univariate: p = 0.046)-and remained an independent prognostic factor in multivariate analysis (p = 0.017). Propensity score-adjusted analysis with CIRT versus FSRT as the dependent variable yielded a significant overall survival advantage for the CIRT group (median OS 8.9 versus 7.2 months, p = 0.041, 1‑year survival 29 versus 10%). Adverse events (AE) were evaluated for both subgroups. For the FSRT group no toxicity ≥ grade 4 occurred. For the CIRT subgroup no grade 5 AE occurred, but 1 patient developed a grade 4 radionecrosis. We encountered 4 grade 3 toxicities. One patient developed a zoster at the trunk, 2 progressed in their paresis, and 1 featured progressive dysesthesia., Conclusion: In conclusion, carbon ion treatment is a safe and feasible treatment option for recurrent glioblastoma. Due to the retrospective nature of the study and two different dose levels for CIRT or FSRT, the improved outcome in CIRT reirradiation might be an effect of higher biological impact from carbon ions or a simple dose-escalation effect. This hypothesis needs prospective testing in larger patient cohorts. A prospective phase III randomized trial is in preparation at our center., (© 2021. The Author(s).)

Purpose: High-intensity focused ultrasound (HIFU/FUS) has expanded as a noninvasive quantifiable option for hyperthermia (HT). HT in a temperature range of 40-47 °C (thermal dose CEM43 ≥ 25) could work as a sensitizer to radiation therapy (RT). Here, we attempted to understand the tumor radiosensitization effect at the cellular level after a combination treatment of FUS+RT., Methods: An in vitro FUS system was developed to induce HT at frequencies of 1.147 and 1.467 MHz. Human head and neck cancer (FaDU), glioblastoma (T98G), and prostate cancer (PC-3) cells were exposed to FUS in ultrasound-penetrable 96-well plates followed by single-dose X‑ray irradiation (10 Gy). Radiosensitizing effects of FUS were investigated by cell metabolic activity (WST‑1 assay), apoptosis (annexin V assay, sub-G1 assay), cell cycle phases (propidium iodide staining), and DNA double-strand breaks (γH2A.X assay)., Results: The FUS intensities of 213 (1.147 MHz) and 225 W/cm 2 (1.467 MHz) induced HT for 30 min at mean temperatures of 45.20 ± 2.29 °C (CEM43 = 436 ± 88) and 45.59 ± 1.65 °C (CEM43 = 447 ± 79), respectively. FUS improves the effect of RT significantly by reducing metabolic activity in T98G cells 48 h (RT: 96.47 ± 8.29%; FUS+RT: 79.38 ± 14.93%; p = 0.012) and in PC-3 cells 72 h (54.20 ± 10.85%; 41.01 ± 11.17%; p = 0.016) after therapy, but not in FaDu cells. Mechanistically, FUS+RT leads to increased apoptosis and enhancement of DNA double-strand breaks compared to RT alone in T98G and PC-3 cells., Conclusion: Our in vitro findings demonstrate that FUS has good potential to sensitize glioblastoma and prostate cancer cells to RT by mainly enhancing DNA damage., (© 2021. The Author(s).)

Background: Magnetic resonance imaging (MRI) and amino acid positron-emission tomography (PET) of the brain contain a vast amount of structural and functional information that can be analyzed by machine learning algorithms and radiomics for the use of radiotherapy in patients with malignant brain tumors., Methods: This study is based on comprehensive literature research on machine learning and radiomics analyses in neuroimaging and their potential application for radiotherapy in patients with malignant glioma or brain metastases., Results: Feature-based radiomics and deep learning-based machine learning methods can be used to improve brain tumor diagnostics and automate various steps of radiotherapy planning. In glioma patients, important applications are the determination of WHO grade and molecular markers for integrated diagnosis in patients not eligible for biopsy or resection, automatic image segmentation for target volume planning, prediction of the location of tumor recurrence, and differentiation of pseudoprogression from actual tumor progression. In patients with brain metastases, radiomics is applied for additional detection of smaller brain metastases, accurate segmentation of multiple larger metastases, prediction of local response after radiosurgery, and differentiation of radiation injury from local brain metastasis relapse. Importantly, high diagnostic accuracies of 80-90% can be achieved by most approaches, despite a large variety in terms of applied imaging techniques and computational methods., Conclusion: Clinical application of automated image analyses based on radiomics and artificial intelligence has a great potential for improving radiotherapy in patients with malignant brain tumors. However, a common problem associated with these techniques is the large variability and the lack of standardization of the methods applied.

Purpose: Purpose of this study was to investigate outcome and toxicity of re-irradiation for recurrent primary glioblastoma (rGBM). We evaluated a group of patients with rGBM and identical primary treatment comprising adjuvant radiotherapy (30 × 2 Gy) with concurrent temozolomide (TMZ)., Methods: In this retrospective study of 46 patients, all received adjuvant or definitive normofractionated radiotherapy to a pretreated area, some with concurrent chemotherapy. Impact of different clinical, histological, or epidemiological factors on survival and radiation toxicity was reviewed., Results: Of 46 patients, 40 completed the intended therapy. Overall survival (OS) was 20 months (range 6-72 months). Overall survival and progression-free survival after re-irradiation (OS2 and PFS2) were 9.5 and 3.4 months (range 2-40 and 0.7-44 months). Simultaneous systemic therapy improved PFS2 and OS2 (4.3 vs. 2.0, p < 0.001 and 12 vs. 4 months, p = 0.13, respectively). Therapy with TMZ or bevacizumab improved PFS2 vs. nitrosureas (6.6 vs. 2.9, p = 0.03 and 5.1 vs. 2.9 months, p = 0.035, respectively). TMZ also improved PFS2 and OS2 vs. all other systemic therapies (6.6 vs. 4, p < 0.001 and 17 vs. 10 months, p = 0.1). In a subgroup analysis for patients with methylation of the MGMT promoter, doses of >36 Gy as well as TMZ vs. no systemic therapy improved PFS2 (p = 0.045 and p = 0.03, respectively). 27.5% of all patients had no acute toxicity. Three patients with acute and four patients with late grade 3 toxicities were reported., Conclusion: Normofractionated radiotherapy is a feasible option for rGBM with a good toxicity profile. Simultaneously applied systemic therapy was associated with improved outcome. For MGMT promoter-methylated histology, higher radiation doses improved survival.

Purpose: To report our results of computed tomography-guided interstitial high-dose-rate (HDR) brachytherapy (BRT) in the treatment of patients with recurrent inoperable glioblastoma multiforme (GBM)., Patients and Methods: Between 1995 and 2014, 135 patients were treated with interstitial HDR BRT for inoperable recurrent GBM located within previously irradiated volumes. Patient's median age was 57.1 years (14-82 years). All patients were pretreated with surgery, postoperative external beam radiation therapy (EBRT) and systemic chemotherapy (ChT). The median recurrent tumor volume was 42 cm 3 (2-207 cm 3 ). The prescribed HDR dose was median 40 Gy (30-50 Gy) delivered in twice-daily fractions of 5.0 Gy over consecutive days. No repeat surgery or ChT was administered in conjunction with BRT. Survival from BRT, progression-free survival (PFS), toxicity as well as the impact of several prognostic factors were evaluated., Results: At a median follow-up of 9.2 months, the median overall survival following BRT and the median PFS were 9.2 and 4.6 months, respectively. Of the prognostic variables evaluated in univariate analysis, extent of surgery at initial diagnosis, tumor volume at recurrence, as well as time from EBRT to BRT reached statistical significance, retained also in multivariate analysis. Eight patients (5.9%) developed treatment-associated complications including intracerebral bleeding in 4 patients (2.9%), symptomatic focal radionecrosis in 3 patients (2.2%), and severe convulsion in 1 patient (0.7%)., Conclusions: For patients with recurrent GBM, interstitial HDR BRT is an effective re-irradiation method for even larger tumors providing palliation without excessive toxicity.

Background: For glioblastoma (GBM), multiple prognostic factors have been identified. Semantic imaging features were shown to be predictive for survival prediction. No similar data have been generated for the prediction of progression. The aim of this study was to assess the predictive value of the semantic visually accessable REMBRANDT [repository for molecular brain neoplasia data] images (VASARI) imaging feature set for progression and survival, and the creation of joint prognostic models in combination with clinical and pathological information., Methods: 189 patients were retrospectively analyzed. Age, Karnofsky performance status, gender, and MGMT promoter methylation and IDH mutation status were assessed. VASARI features were determined on pre- and postoperative MRIs. Predictive potential was assessed with univariate analyses and Kaplan-Meier survival curves. Following variable selection and resampling, multivariate Cox regression models were created. Predictive performance was tested on patient test sets and compared between groups. The frequency of selection for single variables and variable pairs was determined., Results: For progression free survival (PFS) and overall survival (OS), univariate significant associations were shown for 9 and 10 VASARI features, respectively. Multivariate models yielded concordance indices significantly different from random for the clinical, imaging, combined, and combined + MGMT models of 0.657, 0.636, 0.694, and 0.716 for OS, and 0.602, 0.604, 0.633, and 0.643 for PFS. "Multilocality," "deep white-matter invasion," "satellites," and "ependymal invasion" were over proportionally selected for multivariate model generation, underlining their importance., Conclusions: We demonstrated a predictive value of several qualitative imaging features for progression and survival. The performance of prognostic models was increased by combining clinical, pathological, and imaging features.

Purpose: The prognosis for high-grade glioma (HGG) patients is poor; thus, treatment-related side effects need to be minimized to conserve quality of life and functionality. Advanced techniques such as proton radiation therapy (PRT) and volumetric-modulated arc therapy (VMAT) may potentially further reduce the frequency and severity of radiogenic impairment., Materials and Methods: We retrospectively assessed 12 HGG patients who had undergone postoperative intensity-modulated proton therapy (IMPT). VMAT and 3D conformal radiotherapy (3D-CRT) plans were generated and optimized for comparison after contouring crucial neuronal structures important for neurogenesis and neurocognitive function. Integral dose (ID), homogeneity index (HI), and inhomogeneity coefficient (IC) were calculated from dose statistics. Toxicity data were evaluated., Results: Target volume coverage was comparable for all three modalities. Compared to 3D-CRT and VMAT, PRT showed statistically significant reductions (p < 0.05) in mean dose to whole brain (-20.2 %, -22.7 %); supratentorial (-14.2 %, -20,8 %) and infratentorial (-91.0 %, -77.0 %) regions; brainstem (-67.6 %, -28.1 %); pituitary gland (-52.9 %, -52.5 %); contralateral hippocampus (-98.9 %, -98.7 %); and contralateral subventricular zone (-62.7 %, -66.7 %, respectively). Fatigue (91.7 %), radiation dermatitis (75.0 %), focal alopecia (100.0 %), nausea (41.7 %), cephalgia (58.3 %), and transient cerebral edema (16.7 %) were the most common acute toxicities., Conclusion: Essential dose reduction while maintaining equal target volume coverage was observed using PRT, particularly in contralaterally located critical neuronal structures, areas of neurogenesis, and structures of neurocognitive functions. These findings were supported by preliminary clinical results confirming the safety and feasibility of PRT in HGG.

Objectives: Marital status is a well-described prognostic factor in patients with gliomas but the observed survival difference is unexplained in the available population-based studies., Methods: A series of 57 elderly glioblastoma patients (≥70 years) were analyzed retrospectively. Patients received radiotherapy or chemoradiation with temozolomide. The prognostic significance of marital status was assessed. Disease complications, toxicity, and treatment delivery were evaluated in detail., Results: Overall survival was significantly higher in married than in unmarried patients (median, 7.9 vs. 4.0 months; p = 0.006). The prognostic significance of marital status was preserved in the multivariate analysis (HR, 0.41; p = 0.011). Married patients could receive significantly higher daily temozolomide doses (mean, 53.7 mg/m² vs. 33.1 mg/m²; p = 0.020), were more likely to receive maintenance temozolomide (45.7 % vs. 11.8 %; p = 0.016), and had to be hospitalized less frequently during radiotherapy (55.0 % vs. 88.2 %; p = 0.016). Of the patients receiving temozolomide, married patients showed significantly lower rates of hematologic and liver toxicity. Most complications were infectious or neurologic in nature. Complications of any grade were more frequent in unmarried patients (58.8 % vs. 30.0 %; p = 0.041) with the incidence of grade 3-5 complications being particularly elevated (47.1 % vs. 15.0 %; p = 0.004)., Conclusion: We found poorer treatment delivery as well as an unexpected severe increase in toxicity and disease complications in elderly unmarried glioblastoma patients. Marital status may be an important predictive factor for clinical decision-making and should be addressed in further studies.

Aim: To evaluate the role of magnetic resonance imaging (MRI) as a predictor for the clinical course in patients with glioblastoma., Patients and Methods: In 64 patients with glioblastoma undergoing (chemo)radiotherapy MRI studies were obtained before radiation, after 30 gray (Gy), after 60 Gy and during follow-up. MRI findings were assigned to categories: definite progression, questionable progression, no change. Patients were followed clinically., Results: At 30 Gy, 23 of 64 patients (36 %) demonstrated definite (dp; n = 15) or questionable (qp; n = 8) progression; in 41/64 (64 %) no change was found compared with preradiation MRI. After radiotherapy at 60 Gy, 26 of 64 (41 %) patients showed dp (n = 18) or qp (n = 8). In 2 cases with qp at the 30 Gy MRI, progress was unquestionable in the 60 Gy MRI study. In the 64 patients, 5 of the 60 Gy MRIs showed dp/qp after being classified as no change at the 30 Gy MRI, 2 of the 30 Gy MRIs showed qp, while the 60 Gy MRI showed tumour regression and 3 fulfilled the criteria for pseudoprogression during ongoing radiotherapy. The 30 Gy study allowed for prognostic stratification: dp/qp compared to stable patients showed median survival of 10.5 versus 20 months., Conclusion: MR follow-up after 30 Gy in patients undergoing (chemo)radiotherapy for glioblastoma allows prognostic appraisal. Pseudoprogression has to be taken into account, though rare in our setting. Based on these findings, early discussion of treatment modification is possible.

Background: In 20 patients with high-grade gliomas, we compared two methods of planning for volumetric-modulated arc therapy (VMAT): simultaneous integrated boost (SIB) vs. sequential boost (SEB). The investigation focused on the analysis of dose distributions in the target volumes and the organs at risk (OARs)., Method: After contouring the target volumes [planning target volumes (PTVs) and boost volumes (BVs)] and OARs, SIB planning and SEB planning were performed. The SEB method consisted of two plans: in the first plan the PTV received 50 Gy in 25 fractions with a 2-Gy dose per fraction. In the second plan the BV received 10 Gy in 5 fractions with a dose per fraction of 2 Gy. The doses of both plans were summed up to show the total doses delivered. In the SIB method the PTV received 54 Gy in 30 fractions with a dose per fraction of 1.8 Gy, while the BV received 60 Gy in the same fraction number but with a dose per fraction of 2 Gy., Results: All of the OARs showed higher doses (Dmax and Dmean) in the SEB method when compared with the SIB technique. The differences between the two methods were statistically significant in almost all of the OARs. Analysing the total doses of the target volumes we found dose distributions with similar homogeneities and comparable total doses., Conclusion: Our analysis shows that the SIB method offers advantages over the SEB method in terms of sparing OARs.

Background: Radiotherapy has been reported to promote the invasion of glioblastoma cells; however, the underlying mechanisms remain unclear. Here, we investigated the role of the Wnt/β-catenin pathway in radiation-induced invasion of glioblastoma cells., Methods: U87 cells were irradiated with 3 Gy or sham irradiated in the presence or absence of the Wnt/β-catenin pathway inhibitor XAV 939. Cell invasion was determined by an xCELLigence real-time cell analyser and matrigel invasion assays. The intracellular distribution of β-catenin in U87 cells with or without irradiation was examined by immunofluorescence and Western blotting of nuclear fractions. We next investigated the effect of irradiation on Wnt/β-catenin pathway activity using TOP/FOP flash luciferase assays and quantitative polymerase chain reaction analysis of β-catenin target genes. The expression levels and activities of two target genes, matrix metalloproteinase (MMP)-2 and MMP-9, were examined further by Western blotting and zymography., Results: U87 cell invasiveness was increased significantly by ionizing radiation. Interestingly, ionizing radiation induced nuclear translocation and accumulation of β-catenin. Moreover, we found increased β-catenin/TCF transcriptional activities, followed by up-regulation of downstream genes in the Wnt/β-catenin pathway in irradiated U87 cells. Importantly, inhibition of the Wnt/β-catenin pathway by XAV 939, which promotes degradation of β-catenin, significantly abrogated the pro-invasion effects of irradiation. Mechanistically, XAV 939 suppressed ionizing radiation-triggered up-regulation of MMP-2 and MMP-9, and inhibited the activities of these gelatinases., Conclusion: Our data demonstrate a pivotal role of the Wnt/β-catenin pathway in ionizing radiation-induced invasion of glioblastoma cells, and suggest that targeting β-catenin is a promising therapeutic approach to overcoming glioma radioresistance.

Background: Treatment of recurrent glioblastoma (rGBM) remains an unsolved clinical problem. Reirradiation (re-RT) can be used to treat some patients with rGBM, but as a monotherapy it has only limited efficacy. Chloroquine (CQ) is an anti-malaria and immunomodulatory drug that may inhibit autophagy and increase the radiosensitivity of GBM., Patients and Methods: Between January 2012 and August 2013, we treated five patients with histologically confirmed rGBM with re-RT and 250 mg CQ daily., Results: Treatment was very well tolerated; no CQ-related toxicity was observed. At the first follow-up 2 months after finishing re-RT, two patients achieved partial response (PR), one patient stable disease (SD), and one patient progressive disease (PD). One patient with reirradiated surgical cavity did not show any sign of PD., Conclusion: In this case series, we observed encouraging responses to CQ and re-RT. We plan to conduct a CQ dose escalation study combined with re-RT.

Background and Purpose: The aim of this study was to estimate a radiobiological set of parameters from the available clinical data on glioblastoma (GB)., Patients and Methods: A number of clinical trial outcomes from patients affected by GB and treated with surgery and adjuvant radiochemotherapy were analyzed to estimate a set of radiobiological parameters for a tumor control probability (TCP) model. The analytical/graphical method employed to fit the clinical data allowed us to estimate the intrinsic tumor radiosensitivity (α), repair capability (b), and repopulation doubling time (T d ) in a first phase, and subsequently the number of clonogens (N) and kick-off time for accelerated proliferation (T(k)). The results were used to formulate a hypothesis for a schedule expected to significantly improve local control. The 95 % confidence intervals (CI(95 %)) of all parameters are also discussed., Results: The pooled analysis employed to estimate the parameters summarizes the data of 559 patients, while the studies selected to verify the results summarize data of 104 patients. The best estimates and the CI(95 %) are α = 0.12 Gy⁻¹ (0.10-0.14), b = 0.015 Gy⁻² (0.013-0.020), α/b = 8 Gy (5.0-10.8), T(d)  = 15.4 days (13.2-19.5), N = 1.10⁴(1.2.10³ - 1.10⁵), and T(k)  = 37 days (29-46). The dose required to offset the repopulation occurring after 1 day (D(prolif)) and starting after T k was estimated as 0.30 Gy/day (0.22-0.39)., Conclusion: The analysis confirms a high value for the α/b ratio. Moreover, a high intrinsic radiosensitivity together with a long kick-off time for accelerated repopulation and moderate repopulation kinetics were found. The results indicate a substantial independence of the duration of the overall treatment and an improvement in the treatment effectiveness by increasing the total dose without increasing the dose fraction.

Introduction: Diffusion tensor imaging (DTI) is an MR-based technique that may better detect the peritumoural region than MRI. Our aim was to explore the feasibility of using DTI for target volume delineation in glioblastoma patients., Materials and Methods: MR tensor tracts and maps of the isotropic (p) and anisotropic (q) components of water diffusion were coregistered with CT in 13 glioblastoma patients. An in-house image processing program was used to analyse water diffusion in each voxel of interest in the region of the tumour. Tumour infiltration was mapped according to validated criteria and contralateral normal brain was used as an internal control. A clinical target volume (CTV) was generated based on the T1-weighted image obtained using contrast agent (T1Gd), tractography and the infiltration map. This was compared to a conventional T2-weighted CTV (T2-w CTV)., Results: Definition of a diffusion-based CTV that included the adjacent white matter tracts proved highly feasible. A statistically significant difference was detected between the DTI-CTV and T2-w CTV volumes (p < 0.005, t = 3.480). As the DTI-CTVs were smaller than the T2-w CTVs (tumour plus peritumoural oedema), the pq maps were not simply detecting oedema. Compared to the clinical planning target volume (PTV), the DTI-PTV showed a trend towards volume reduction. These diffusion-based volumes were smaller than conventional volumes, yet still included sites of tumour recurrence., Conclusion: Extending the CTV along the abnormal tensor tracts in order to preserve coverage of the likely routes of dissemination, whilst sparing uninvolved brain, is a rational approach to individualising radiotherapy planning for glioblastoma patients.

Background: The incidence of glioblastoma (GBM) in the elderly population is currently increasing, with a peak seen between 65 and 84 years. The optimal treatment in terms of both efficacy and quality of life still remains a relevant and debated issue today. The purpose of our study was to evaluate the feasibility of short-course hypofractionated accelerated radiotherapy (HART) in GBM patients aged over 70 years and with a good Karnofsky performance score (KPS)., Methods: A review of medical records at the "Istituto Neurologico C. Besta" was undertaken; patients aged ≥ 70 years who had undergone adjuvant HART for GBM between January 2000 and January 2004 were included in the study. HART was administered to a total dose of 45 Gy, 2.5 Gy/fraction, in three daily fractions for three consecutive days/cycle fractions each, delivered in two cycles (split 15 days)., Results: A total of 33 patients were evaluable for the current analysis. Median follow-up was 10 months. According to CTCAE (version 3.0) criteria, none of the patients developed radiation-induced neurological status deterioration or necrosis. KPS evaluation after HART was found to be stable in 73 % of patients, improved in 24 %, and worse in 3 %. The median overall survival time of the entire study population was 8 months (range 2-24)., Conclusions: Our findings suggest that a hypofractionated accelerated schedule can be a safe and effective option in the treatment of GBM in the elderly.

Purpose: Dose escalations above 60 Gy based on MRI have not led to prognostic benefits in glioblastoma patients yet. With positron emission tomography (PET) using [(18)F]fluorethyl-L-tyrosine (FET), tumor coverage can be optimized with the option of regional dose escalation in the area of viable tumor tissue., Methods and Materials: In a prospective phase II study (January 2008 to December 2009), 22 patients (median age 55 years) received radiochemotherapy after surgery. The radiotherapy was performed as an MRI and FET-PET-based integrated-boost intensity-modulated radiotherapy (IMRT). The prescribed dose was 72 and 60 Gy (single dose 2.4 and 2.0 Gy, respectively) for the FET-PET- and MR-based PTV-FET((72 Gy)) and PTV-MR((60 Gy)). FET-PET and MRI were performed routinely for follow-up. Quality of life and cognitive aspects were recorded by the EORTC-QLQ-C30/QLQ Brain20 and Mini-Mental Status Examination (MMSE), while the therapy-related toxicity was recorded using the CTC3.0 and RTOG scores., Results: Median overall survival (OS) and disease-free survival (DFS) were 14.8 and 7.8 months, respectively. All local relapses were detected at least partly within the 95% dose volume of PTV-MR((60 Gy)). No relevant radiotherapy-related side effects were observed (excepted alopecia). In 2 patients, a pseudoprogression was observed in the MRI. Tumor progression could be excluded by FET-PET and was confirmed in further MRI and FET-PET imaging. No significant changes were observed in MMSE scores and in the EORTC QLQ-C30/QLQ-Brain20 questionnaires., Conclusion: Our dose escalation concept with a total dose of 72 Gy, based on FET-PET, did not lead to a survival benefit. Acute and late toxicity were not increased, compared with historical controls and published dose-escalation studies.

Background and Purpose: To evaluate the influence of serum hemoglobin level prior to radiotherapy and other prognostic factors on survival in patients with high-grade gliomas., Material and Methods: From 2001-2010, we retrospectively evaluated a total of 48 patients with malignant glioma treated with surgery and postoperative radiochemotherapy with temozolomide. A total of 37 of 48 patients received sequential temozolomide. Hemoglobin levels were assayed before radiotherapy in all patients. The Kaplan-Meier method was applied to estimate the overall survival, while the log-rank test was applied to evaluate the differences on survival probability between prognostic subgroups., Results: Results were assessed in 43 patients. The median overall survival time was 18 months (95% confidence interval: 12-40 months). The 1- and 2-year survival rates were 62.2% and 36.3%, respectively. The prognostic factors analyzed were gender, age, extent of surgery, performance status before and after radiotherapy, sequential chemotherapy, hemoglobin level, and methylation of the O-6-methylguanine-DNA methyltransferase gene (MGMT). In univariate analysis, the variables significantly related to survival were performance status before and after radiotherapy, sequential chemotherapy, and hemoglobin level. The median overall survival in patients with a hemoglobin level ≤ 12 g/dl was 12 months and 23 months in patients with a hemoglobin level > 12 g/dl. The 1- and 2-year survival rates were 46.7% and 20.0%, respectively, for patients with a hemoglobin level ≤ 12 mg/dl and 69.6% and 45.7%, respectively, for patients with a hemoglobin level > 12 g/dl., Conclusion: Our results confirm the impact of well-known prognostic factors on survival. In this research, it was found that a low hemoglobin level before radiotherapy can adversely influence the prognosis of patients with malignant gliomas.

Background: The objective of this retrospective analysis was to assess long-term outcome and prognostic factors of unselected patients treated for glioblastoma (GB) at a single center with surgery, standard radiotherapy (RT), and concomitant temozolomide (TMZ). From 1999-2005, the institutional protocol included surgery and RT with TMZ. From 2005 on, adjuvant TMZ was routinely added., Patients and Methods: Between April 1999 and September 2009, 181 patients with GB were treated with RT (60 Gy in 30 fractions) and concomitant TMZ (75 mg/m2/day throughout RT). Biopsy only had been performed in 53 patients (29.3%), 128 patients (70.7%) had undergone resection, which was complete based on postoperative MRI in 51 patients (28.2%). Adjuvant TMZ was applied in 67 of 181 patients (37%)., Results: Median overall survival (OS) and progression-free survival (PFS) were 15.0 (95% CI, 13.1-16.8) and 7.2 months (95% CI, 5.9-8.5), respectively. After complete resection, partial/subtotal resection and biopsy, median OS was 23.20, 14.75, and 7.89 months (p<0.001), respectively. In multivariate Cox proportional hazards regression models, extent of resection (p<0.0001), Karnofsky's performance score (p<0.0001) and adjuvant TMZ (p=0.001) were significant independent prognostic factors for OS. RT with concomitant TMZ was well tolerated in the majority of patients and could be completed as scheduled in 146 patients (80.7%), while 11 patients (6.1%) discontinued RT. Another 35 patients (19.3%) interrupted concomitant chemotherapy., Conclusion: RT with concomitant TMZ is a feasible regimen with acceptable toxicity in routine practice. Our data are compatible with a beneficial effect of adjuvant TMZ on OS and PFS.

Background: The goal of this study was to evaluate accelerated radiotherapy with and without temozolomide (TMZ) for glioblastoma multiforme (GBM)., Methods: This retrospective analysis evaluated 86 patients with histologically proven GBM who were treated with accelerated radiotherapy of 1.8 Gy twice daily to a total dose of 54 Gy within 3 weeks. Median age was 62 years and median Karnofsky index was 90. A total of 41 patients received radiotherapy only from 2002-2005 and 45 patients were treated with TMZ concomitantly and after radiotherapy from 2005-2007., Results: Median overall survival (OS) was 12.5 months and 2-year OS was 15.4%. Patient characteristics were well balanced between the two groups except for better performance status (p = 0.05) and higher frequency of retreatment for the first recurrence (p = 0.02) in the TMZ group. Age at diagnosis (HR 2.83) and treatment with TMZ (HR 0.60) were correlated with OS in the multivariate analysis: treatment with and without TMZ resulted in median OS of 16 months and 11.3 months, respectively. Hematological toxicity grade > II was observed in 2/45 patients and 5/37 patients during simultaneous radiochemotherapy and adjuvant TMZ., Conclusion: TMZ added to accelerated radiotherapy for GBM resulted in prolonged overall survival with low rates of severe hematological toxicity.

Purpose: The aim of this study was to evaluate whether the omega-3 polyunsaturated fatty acid cis-5,8,11,14,17-eicosapentanoic acid (EPA) can enhance the radiosensitivity of different human tumor cell lines., Materials and Methods: Colon adenocarcinoma cells HT-29, and two glioblastoma multiforme tumor cells T98G and U251 were cultured under standard conditions. Cell growth was observed during administration with different concentrations of EPA, using it as the free fatty acid dissolved in ethanol or bound to bovine serum albumin. To investigate the influence of EPA (free and bound) on radiosensitivity, tumor cells were pretreated 30 minutes or 24 hours prior to irradiation with the fatty acid. Cell survival was measured by colony-forming assays., Results: When combined with irradiation, incubation with EPA was found to result in enhanced radiosensitivity with substantial variation: while there was strong radiosensitization for HT-29 and U251 cells, almost no effect for T98G cells was observed. A marked radiosensitization was clearly dependent on the treatment schedule., Conclusion: The observations suggest that EPA is not only a nutritional adjuvant but also may be a potential candidate to enhance the efficacy of irradiation on human cancer cells.

Purpose: determine the value of MR studies in patients undergoing radiotherapy for glioblastomas pre and during radiotherapy to predict the clinical course., Patients and Methods: MR follow-up studies were performed in 33 patients with glioblastomas before radiotherapy, after 30 Gy, after 60 Gy, and in the treatment follow-up. Findings on MR were categorized into: definite progress, questionable progress, status idem. Patients were followed clinically (median for 11 months)., Results: after 30 Gy 23/33 (70%) of the MR examination showed status idem. 10/33 (30%) demonstrated definite (n = 6) or questionable (n = 4) progress. Further tumor progress was faster in these patients and patients succumb to their disease earlier (9 vs. 22 months). The 60 Gy study showed definite (n = 8) and questionable (n = 6) progress in 14/33 (42%) cases. All these tumors were progressing faster and were associated with a comparatively reduced life expectancy., Conclusion: MR follow-up studies after 30 Gy in patients undergoing radiotherapy for glioblastomas allow for prognostic appraisal, and potentially early modification of treatment.

Background: Standard treatment of glioblastoma multiforme consists of postoperative radiochemotherapy with temozolomide, followed by a 6-month chemotherapy. Serious hematologic complications are rarely reported., Case Report and Results: The authors present the case of a 61-year-old female patient with glioblastoma multiforme treated with external-beam radiation therapy and concomitant temozolomide. After completion of treatment, the patient developed symptoms of serious aplastic anemia that eventually led to death due to prolonged neutro- and thrombocytopenia followed by infectious complications., Conclusion: Lethal complications following temozolomide are, per se, extremely rare, however, a total of four other cases of aplastic anemia have been reported in the literature so far.

Purpose: To investigate the potential of (18)F-fluoroethyltyrosine-positron emission tomography-((18)F-FET-PET-)based dose painting by numbers with protons., Material and Methods: Due to its high specificity to brain tumor cells, FET has a high potential to serve as a target for dose painting by numbers. Biological image-based dose painting might lead to an inhomogeneous dose prescription. For precise treatment planning of such a prescribed dose, an intensity-modulated radiotherapy (IMRT) algorithm including a Monte Carlo dose-calculation algorithm for spot-scanning protons was used. A linear tracer uptake to dose model was used to derive a dose prescription from the (18)F-FET-PET. As a first investigation, a modified modulation transfer function (MTF) of protons was evaluated and compared to the MTF of photons. In a clinically adapted planning study, the feasibility of (18)F-FET-PET-based dose painting with protons was demonstrated using three patients with glioblastome multiforme. The resulting dose distributions were evaluated by means of dose-difference and dose-volume histograms and compared to IMRT data., Results: The MTF for protons was constantly above that for photons. The standard deviations of the dose differences between the prescribed and the optimized dose were smaller in case of protons compared to photons. Furthermore, the escalation study showed that the doses within the subvolumes identified by biological imaging techniques could be escalated remarkably while the dose within the organs at risk was kept at a constant level., Conclusion: The presented investigation fortifies the feasibility of (18)F-FET-PET-based dose painting with protons.

Purpose: To investigate technical feasibilities of noncoplanar proton-beam therapy (PBT) on dose reduction to critical organs., Material and Methods: The degree of mechanical precision, rotational limitations of the gantry and the treatment couch were evaluated, and dose-volume histograms were compared for noncoplanar and coplanar PBT. Following these studies, three patients with tumors proximal to the optic nerve underwent noncoplanar PBT., Results: Noncoplanar PBT offered advantage in dose reduction to the optic nerve when compared to coplanar therapy. This advantage was more significant if the tumor reduced in size during treatment. None experienced radiation injury to the optic nerve during a short follow-up time of 7-12 months., Conclusion: Noncoplanar PBT appears to reduce doses to organs at risk.

Purpose: To assess the feasibility and effectiveness of perioperative high-dose-rate brachytherapy for recurrent malignant gliomas., Patients and Methods: Between 2005 and 2008, 21 patients (14 males and seven females) with relapsed malignant glioma underwent a second surgery followed by a brachytherapy implant in the surgical cavity. Median age was 60 years, and median Karnofsky performance status 80. A single fraction of 18 Gy specified at 5 mm depth was administered perioperatively. Then, the applicator was removed nonsurgically. Mean postoperative hospitalization time was 3 days., Results: At the time of analysis, 15 patients (71%) had died and six (29%) were alive. Median follow-up was 32.3 months. Median overall survival from diagnosis amounted to 21.7 months. Median survival after recurrence was 8.0 months, and 6-month progression-free survival 42%. Patients were stratified into classes according to the prognostic recursive partitioning analysis., Conclusion: Perioperative brachytherapy has proven to be safe and well tolerated in patients with recurrent malignant glioma. No severe toxicity was reported, and the treatment has proven to be effective in symptomatic recurrences of malignant gliomas.

Purpose: To evaluate the efficacy of simultaneous postoperative temozolomide radiochemotherapy in glioblastoma patients., Patients and Methods: From February 2002 to July 2004, n = 65 patients from 11 German centers with macroscopic complete tumor resection were randomized to receive either postoperative radiotherapy alone (RT, n = 35) or postoperative radiotherapy with simultaneous temozolomide (RT + TMZ, n = 30). Patients were stratified according to age (< or =/>50 years) and WHO performance score (0-1 vs. 2). RT consisted of 60 Gy in 30 fractions. In the RT + TMZ arm, oral TMZ was administered daily at a dose of 75 mg/m(2) including weekends (40-42 doses). Adjuvant treatment was not given, but in both arms, patients with recurrent tumors and in good condition (WHO 0-2) were scheduled for salvage chemotherapy with TMZ., Results: The trial was stopped early due to the results of EORTC-study 26981-22981 that showed a survival benefit for the combination of concomitant and adjuvant TMZ compared to radiotherapy alone. In total, 62/65 patients were evaluable. Stratification variables were well balanced (< or = 50 years 26% vs. 20%, WHO 0-1 91% vs. 100%). Neither overall survival (median 17 vs. 15 months) nor progression-free survival (median 7 vs. 6 months) differed significantly between the two arms. In the RT (RT + TMZ) arm, 76% (62%) of the progressing patients received salvage chemotherapy with TMZ, 36% (50%) had a second resection. There was a time-constant trend for increased general quality of life (EORTC questionnaire QLQ C30) and brain-specific quality of life (EORTC questionnaire B20) in the combined arm. Lymphopenia G3-4 was more frequent (33 vs. 6%) in the RT + TMZ arm., Conclusion: After early closure of this trial, a benefit for progression-free survival for simultaneous TMZ radiochemotherapy alone could not be demonstrated. In both arms, salvage therapies were frequently used and probably had a major effect on overall survival.

Purpose: To demonstrate the feasibility of a biologically adapted dose-escalation approach to brain tumors., Material and Methods: Due to the specific accumulation of fluoroethyltyrosine (FET) in brain tumors, (18)F-FET-PET imaging is used to derive a voxel-by-voxel dose distribution. Although the kinetics of (18)F-FET are not completely understood, the authors regard regions with high tracer uptake as vital and aggressive tumor and use a linear dose-escalation function between SUV (standard uptake value) 3 and SUV 5. The resulting dose distribution is then planned using the inverse Monte Carlo treatment- planning system IKO. In a theoretical study, the dose range is clinically adapted from 1.8 Gy to 2.68 Gy per fraction (with a total of 30 fractions). In a second study, the maximum dose of the model is increased step by step from 2.5 Gy to 3.4 Gy to investigate whether a significant dose escalation to tracer-accumulating subvolumes is possible without affecting the shell-shaped organ at risk (OAR). For all dose-escalation levels the dose difference Delta D of each voxel inside the target volume is calculated and the mean dose difference Delta D and their standard deviation sigma Delta D are determined. The dose to the OAR is evaluated by the dose values D OAR 50% and D OAR 5%, which are the dose values not exceeded by 50% and 5% of the volume, respectively., Results: The inhomogeneous dose prescription is achieved with high accuracy (Delta D < 0.03 +/- 0.3 Gy/fraction). The maximum dose can be increased remarkably, without increasing the dose to the OAR (standard deviation of D OAR 50% < 0.02 Gy/fraction and of D OAR 5% < 0.05 Gy/fraction)., Conclusion: Assuming that regions with high tracer uptake can be interpreted as target for radiotherapy, (18)F-FET-PET-based "dose painting by numbers" applied to brain tumors is a feasible approach. The dose, and therefore potentially the chance of tumor control, can be enhanced. The proposed model can easily be transferred to other tracers and tumor entities.

Background and Purpose: Different factors influence glioblastoma patients' prognosis. The aim of this retrospective, explorative analysis was to define the role of recent treatment strategies and to examine the value of different prognostic factors., Patients and Methods: A total of 110 patients was analyzed. Complete resection, partial resection, and biopsy was accomplished in 69, 22, and 19 patients, respectively. 56 patients received conventionally fractionated radiotherapy with a median total dose of 60 Gy, 2 Gy daily. 54 patients received hyperfractionated accelerated radiotherapy with a median total dose of 54 Gy, 2 x 1.8 Gy daily. 20 patients had concomitant temozolomide (50-75 mg/m2/d), and 20 patients concomitant topotecan (0.5 mg/m2 as continuous venous infusion over 21 days). 37 patients received temozolomide as salvage therapy., Results: Median overall (OS) and disease-free survival (DFS) were 8.7 and 4.8 months. After complete resection, partial resection, and biopsy, OS was 9.5, 8.5, and 5.5 months, respectively. OS was 8.5, 13.8, and 8.2 months for radiotherapy alone, concomitant temozolomide, and concomitant topotecan, respectively. Hazard ratio was 0.29 (OS; p = 0.002) and 0.32 (DFS; p = 0.003) for concomitant temozolomide compared to radiotherapy alone. Topotecan led to an increased toxicity. With 9.7 months for conventionally fractionated radiotherapy and 8.1 months for hyperfractionated radiotherapy, OS differed significantly (p = 0.003, log-rank test). OS in patients with RPA (recursive partitioning analysis) score III, IV, V, and VI was 14.1, 10, 9.5, and 5.8 months (p = 0.003, log-rank test). In the univariate (p = 0.0001, log-rank test) and multivariate analysis (p = 0.002, Cox regression), salvage temozolomide led to a statistically significant survival benefit (10.6 vs. 7.7 months)., Conclusion: Concomitant topotecan or the use of hyperfractionated radiotherapy did not show to be superior in outcome in this retrospective analysis. Topotecan led to an increased toxicity. An attempt at complete resection is justified. Temozolomide should be integrated in therapy initially. As salvage therapy, temozolomide is also effective.

Background and Purpose: Computed tomography (CT) and magnetic resonance imaging (MRI) are traditionally used for treatment planning of high-grade glioma. 99m Tc-methoxy-isobutyl-isonitrile (MIBI) single-photon emission computed tomography (SPECT) showed high sensitivity and specificity in literature series. In the present study, it was investigated how the information provided by 99m Tc-MIBI SPECT and MRI fusion could affect target delineation for radiotherapy of high-grade glioma., Patients and Methods: 21 patients with high-grade glioma were studied by MRI and 99m Tc-MIBI SPECT imaging. The gross tumor volume (GTV) was outlined on MRI (MRI-GTV) and SPECT images (SPECT-GTV). Three additional volumes were analyzed: the (MRI+SPECT)-GTV representing the whole amount of MRI-GTV plus SPECT-GTV, the (MRI&SPECT)-GTV identified by the overlapping region of MRI-GTV and SPECT-GTV, and the (SPECT/MRI)-GTV identified by the extension of SPECT-GTV outside MRI-GTV., Results: MRI contrast-enhanced and 99m Tc-MIBI SPECT-positive lesions were found in all 21 patients. The average SPECT-GTV was slightly larger than the average MRI-GTV, with greater difference for resected than for unresected cases. The average increment of (MRI+SPECT)-GTV compared to MRI-GTV was 33%, being significantly higher for resected than for unresected cases (p = 0.006)., Conclusion: The fusion of 99m Tc-MIBI SPECT and MRI significantly affected the delineation of the target volume identified by MRI alone.

Background and Purpose: Recurrences of glioblastoma multiforme (GBM) within previously irradiated volumes pose a serious therapeutic challenge. This retrospective study evaluates the long-term tumor control of recurrent GBM treated with interstitial high-dose-rate brachytherapy (HDR-BRT)., Patients and Methods: Between 1995 and 2003, 84 patients were treated for recurrent cerebral GBM located within previously irradiated volumes. All patients had received adjuvant external radiotherapy following primary surgery, with a focal dose up to 60 Gy. The median recurrent tumor volume was 51 cm(3) (3-207 cm(3)), and the HDR-BRT consisted of an afterloading (192)Ir implant which delivered a median dose of 40 Gy (30-50 Gy). Catheter implantation was implemented using interactive computed tomography (CT) guidance under local anesthesia and sedoanalgesia., Results: After a median follow-up of 61 months, 5/84 patients (6%) were alive. The median post-BRT survival was 37 weeks, and the median overall survival 78 weeks. Moderate to severe complications occurred in 5/84 cases (6%)., Conclusion: For patients with recurrences of GBM within previously irradiated volumes, CT-guided interstitial HDR-BRT is a feasible treatment option that can play an important role in providing palliation.

Background and Purpose: The aim of these experiments was to study the relationship between the previously demonstrated efficacy of carbogen breathing on tumor oxygenation status and the response to radiation assessed by a growth delay assay. This study was also developed to investigate the microenvironmental changes caused by combined treatment compared to irradiation only in regrowing tumors., Material and Methods: A human glioblastoma xenograft tumor line was implanted in nude mice. Irradiations consisted of 10 Gy or 20 Gy with and without carbogen breathing. Several microenvironmental parameters (tumor cell hypoxia, tumor blood perfusion, vascular volume, and microvascular density) were analyzed after immunohistochemical staining. Tumor growth delay was monitored for up to 120 days after treatment., Results: In general, there was no benefit of combined treatment. However, a small subgroup with good response to combined radiation and carbogen treatment was identified showing little hypoxia and mainly necrosis in the regrowing tumors. These microenvironmental characteristics were not seen in tumors of the other treatment groups., Conclusion: The observations suggest that a subgroup of patients, who could potentially benefit from the combined carbogen and radiation treatment, might be identified. However, the heterogeneous response to treatment illustrates the need for selection of patients before start of treatment.

Background and Purpose: Imatinib (Gleevec, Glivec) is an inhibitor of alpha- and beta-platelet-derived growth factor receptors and other tyrosine kinases, that are also associated with the function of growth factors. Imatinib has been approved for the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors and is under investigation for the therapy of several other malignant tumors. Since radiotherapy is an important treatment option in many tumors, combined effects of imatinib and radiation were analyzed here., Material and Methods: In vitro, U87 cells (human glioblastoma), A431 cells (human epidermoid carcinoma), and HUVECs (human umbilical venous endothelial cells) were treated with imatinib alone and in combination with radiation. Clonogenic survival and cell proliferation were determined with and without additional radiation (0-10 Gy). In vivo, U87 and A431 cells (5 x 10(6)) were subcutaneously injected into hind limbs of balb c nu/u mice. Drug and radiation treatments started on day 0 when tumor volumes were approximately 400-500 mm(3). Tumors were treated with 5 x 5 Gy (U87) or 6 x 5 Gy (A431) on consecutive days from day 0. Imatinib was administered orally via the mouse diet starting on day 0 until the end of observation. Tumor growth and microvessel density (CD31 IHC) were analyzed., Results: In vitro, imatinib increased radiosensitivity of U87 and A431 tumor cells as well as HUVECs in both clonogenic and cell number/proliferation assays. The enhancement of radiosensitivity in HUVECs was comparable to that observed in the tumor cells. In vivo, the concurrent and continuous administration of imatinib increased tumor growth delay of fractionated radiotherapy in the carcinoma and the glioblastoma models at reduced microvessel densities. No apparent additional toxicity by the combination of radiation and imatinib versus monotherapies was observed in terms of weight, skin, or general behavior., Conclusion: Imatinib (Gleevec), a "molecular targeted" approved drug for human malignancies, can enhance the tumor growth reduction induced by fractionated radiotherapy in glioblastoma and carcinoma models. The data provides a rationale to further investigate the combination.

Background and Purpose: Higher rates of glucose utilization and glycolysis generally correlate with poor prognosis in several types of malignant tumors. Own earlier studies on model systems demonstrated that the nonmetabolizable glucose analog 2-deoxy-D-glucose (2-DG) could enhance the efficacy of radiotherapy in a dose-dependent manner by selectively sensitizing cancer cells while protecting normal cells. Phase I/II clinical trials indicated that the combination of 2-DG, at an oral dose of 200 mg/kg body weight (BW), with large fractions of gamma-radiation was well tolerated in cerebral glioma patients. Since higher 2-DG doses are expected to improve the therapeutic gain, present studies were undertaken to examine the tolerance and safety of escalating 2-DG dose during combined treatment (2-DG + radiotherapy) in glioblastoma multiforme patients., Patients and Methods: Untreated patients with histologically proven glioblastoma multiforme (WHO criteria) were included in the study. Seven weekly fractions of (60)Co gamma-rays (5 Gy/fraction) were delivered to the tumor volume (presurgical CT/MRI evaluation) plus 3 cm margin. Escalating 2-DG doses (200-250-300 mg/kg BW) were administered orally 30 min before irradiation after overnight fasting. Acute toxicity and tolerance were studied by monitoring the vital parameters and side effects. Late radiation damage and treatment responses were studied radiologically and clinically in surviving patients., Results: Transient side effects similar to hypoglycemia were observed in most of the patients. Tolerance and patient compliance to the combined treatment were very good up to a 2-DG dose of 250 mg/kg BW. However, at the higher dose of 300 mg/kg BW, two out of six patients were very restless and could not complete treatment, though significant changes in the vital parameters were not observed even at this dose. No significant damage to the normal brain tissue was observed during follow-up in seven out of ten patients who received complete treatment and survived between 11 and 46 months after treatment., Conclusion: Oral administration of 2-DG combined with large fractions of radiation (5 Gy/fraction/week) is safe and could be tolerated in glioblastoma patients without any acute toxicity and late radiation damage to the normal brain. Further clinical studies to evaluate the efficacy of the combined treatment are warranted.

Background: Even after surgery and radiotherapy, malignant gliomas still have a poor prognosis. The authors report on their experience with IORT in 71 patients., Patients and Methods: From May 1992 to February 2004, 71 patients with malignant gliomas were treated with IORT. 26 patients suffered from grade III gliomas, 45 patients from glioblastomas (GBM). IORT was carried out using a standard electron tube and 9- to 18-MeV electrons. 52/71 patients who were primarily treated received 20 Gy IORT + 60 Gy postoperative radiotherapy, 19/71 patients with recurrences only received IORT (20-25 Gy)., Results: The complication rates were 1.4% for wound infections and 5.6% for hemorrhage. Median disease-specific survival amounted to 14.9 months (gliomas III) and 14.2 months (GBM). The 2-year survival rates amounted to 26.9% (gliomas III) and 6.8% (GBM; p = 0.0296). Total versus subtotal resection had no significant influence on survival (p = 0.0741), nor had age, sex, tumor site, performance status, size, primary versus recurrence, and radiation dose. A comparison to a conventionally treated patient group did not show a significant survival improvement. 3 months after treatment, initial symptoms had improved in 59% (hemiparesis), 50% (aphasia), 50% (hemianopsia), and 60% (convulsions)., Conclusion: IORT has been shown to be feasible; perioperative complication rates were not increased. Survival was generally not improved compared to a historical control group. Recurrences achieved the same survival as primary tumors, and GBM also had a slightly increased survival, thus being possible indications for IORT.

Background and Purpose: The role of radiochemotherapy in the treatment of primary glioblastoma multiforme is still discussed controversially. To evaluate the feasibility and toxicity of irradiation and concomitant administration of 50 mg/m(2) temozolomide in patients with primary malignant glioma, this phase I/II study was conducted., Patients and Methods: 53 Patients with histologically confirmed WHO grade IV malignant glioma were enrolled into the study. All patients were treated with radiation therapy up to a total dose of 60 Gy using conventional fractionation of 5 x 2.0 Gy/week. Temozolomide was administered orally each therapy day at a dose of 50 mg/m(2)., Results: Prior to radiochemotherapy, complete resection (n = 14), subtotal resection (n = 22) or a biopsy (n = 17) of the tumor was performed. The median time interval between surgery and radiochemotherapy was 21 days. Treatment-related toxicity was very mild. Acute toxicity > grade 2 was observed in one patient who developed grade 4 hemotoxicity. Minor side effects of chemotherapy included nausea and vomiting. No severe late effects were observed. Median progression-free and overall survival were 8 and 19 months, respectively. The overall survival rate was 72% at 1 and 26% at 2 years. Age and extent of surgery significantly influenced survival., Conclusion: The combination of temozolomide plus radiation therapy is feasible and safe in terms of toxicity. Overall survival times were relatively long compared to survival times reported for radiotherapy alone. The application of 50 mg/m(2) of temozolomide can be performed throughout the whole time course without interruption due to side effects and might largely contribute to the prolonged overall survival. Further evaluation is warranted as to which dose of temozolomide is optimal with regard to tumor response and toxicity.

Background: Little is known concerning the relation of porphyrias to radiation treatment for cancer. The recent literature does not report negative outcomes at least in single cases of breast cancer, bladder cancer or in a patient with lymphoma. Theoretically, there is a risk for radiation treatment in cases of porphyrias., Case Report: Two patients with porphyria are described who underwent radiotherapy for glioblastoma multiforme. Case histories, radiation treatment data and the proof of porphyria are given in detail. The patients received a concomitant radiochemotherapy with infusions of ACNU [1-(4-amino-2-methyl-5-pyrimidinyl)-methyl-(2-chloroethyl)-3-nitrosourea] every 6 weeks. The total radiation doses at the ICRU point were 60 and 38 Gy, respectively, given in single daily fractions of 2 Gy., Results: Both patients responded well as far as objective tumor regression is concerned but died early after 7 and 1.5 months following diagnosis. The first patient experienced a large brain necrosis and deterioration of her porphyria. The second patient died of cardiopulmonary insufficiency still during radiotherapy with persistent or even increased signs of porphyria. The tumor showed extensive necrosis already after 38 Gy., Conclusion: In view of annotations in the literature and this case report, caution is advised as for irradiation of brain or nervous tissues in case of porphyrias. Molecular biology data seems to support this warning to some extent.

Background and Purpose: Primary glioblastomas (GBMs) are highly radioresistant, and in contrast to secondary GBMs, they bear wild-type (wt) p53 protein, which is stabilized in a proportion of these tumors. Therefore, it was investigated in vivo whether p53 expression has prognostic value in patients undergoing radiochemotherapy. Additionally, the authors tried to identify, in vitro, subgroups of primary GBM with different susceptibilities to irradiation, on the basis of their p53 and p21 responses to ionizing radiation., Material and Methods: Tumor tissue samples from 31 patients suffering from primary GBM undergoing a combined radiochemotherapy with topotecan were investigated. The percentage of cells expressing p53 protein was determined immunohistochemically. Additionally, primary cultures from eleven primary GBMs were established and investigated. p53 and p21 expressions were evaluated before irradiation with 10 Gy and at 2 and 8 h after irradiation. p53 protein expression was measured by Western analysis and p21 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR)., Results: The percentage of p53-positive cells within the tumor specimens obtained from the 31 patients ranged from 0% to 28%, the median value being 4.3%. No significant correlation with disease-free survival or overall survival was found. In vitro, p53 protein was detected in seven of eleven cultures from primary GBM. After irradiation a decrease in p53 protein expression was seen in six of the seven p53-positive cultures. Half of the cultures (two of four) without basal p53 expression showed an increase in p53 expression after irradiation. Basal overexpression of p21 was detected in six of the eleven cultures; in four out of six irradiation led to a decrease in p21 expression. In all cell lines (five of eleven) initially showing absent p21 expression, irradiation induced p21 expression. Despite these responses, G1 arrest was not detectable in any of the GBM cultures., Conclusion: p53 protein expression in vivo does not correlate with the outcome of patients with primary GBM. Therefore, p53 protein content per se does not appear to be a helpful prognostic factor for prognosis-adapted therapy in primary GBM. By contrast, primary GBM cells in vitro show different and independent responses in their p53 and p21 pathways to ionizing radiation. The failure of G1 arrest seems to be due to a functional defect in the p53 pathway, either because p21 was not induced or because of an unidentified defect downstream from p21.

Background: Extracranial seeding of glioblastoma multiforme (GBM) is very rare and its development depends on several factors. This case report describes two patients suffering from GBM with spinal seeding. In both cases, the anatomic localization of the primary tumor close to the cerebrospinal fluid (CSF) was the main factor for spinal seeding., Case Reports: Two patients with GBM and spinal seeding are presented. After diagnosis of spinal seeding, both patients were highly symptomatic from their spinal lesions. Case 1 experienced severe pain requiring opiates, and case 2 had paresis of lower limbs as well as urinary retention/incontinence. Both patients were treated with spinal radiation therapy. Nevertheless, they died 3 months after diagnosis of spinal seeding., Results: In both patients the diagnosis of spinal seeding was made at the time of cranial recurrence. Both tumors showed close contact to the CSF initially. Even though the patients underwent intensive treatment, it was not possible to keep them in a symptom-free state., Conclusion: Because of short survival periods, patients deserve optimal pain management and dedicated palliative care.

Purpose: Analysis of the results of radiotherapy in a large group of cerebral gliomas with identification of prognostic factors and the outcome with respect to different decades of treatment., Patients and Methods: Two decades (1979-1999) of radiotherapy in supratentorial astrocytic and oligodendroglial tumors (n = 821) at the University Hospital Groningen were retrospectively evaluated. Prognostic factors for survival were analyzed. Two decades of radiotherapy treatment were compared with respect to radiotherapy dose and treatment-field design., Results: Glioblastoma multiforme, including gliosarcoma, was the most frequent supratentorial glioma (n = 442) with a poor survival, i.e., median survival time (MST) 7 months, especially in patients > 50 years of age and with poor performance. Patients with good performance were selected for radiotherapy with an optimum dose of 60 Gy local-field irradiation. However, in patients with poor prognosis, no radiotherapy was applied or a shorter treatment scheme was given. Anaplastic astrocytomas (n = 131) were treated in the same way as glioblastoma multiforme. Over time, a decrease in radiation dose (from 60 to 45 Gy) and from whole brain irradiation to local-field treatment was observed, following the literature. In low-grade gliomas, prognostic factors for survival were age, performance, and extent of resection. Gemistocytic astrocytoma (n = 15) had an inferior survival compared to astrocytoma (MST 46 vs. 54 months), but a superior survival compared to anaplastic astrocytoma (MST 10 months). The presence of an oligodendroglial component in a glioma implied a superior survival compared to the astrocytic gliomas. The inherent biology of the glioma is reflected by the study of recurrent tumors with progression to higher grades of malignancy in 32-40% and by the histology of recurrent oligodendroglial tumors. In comparing two decades of radiotherapy in gliomas, no differences in survival were observed despite the technological improvements. However, reduction in long-term side effects was not evaluated, especially in low-grade gliomas which were treated in the second decade of the study with local fields only and a reduced radiotherapy dose using computerized three-dimensional (3-D) planning., Conclusion: Radiotherapy does not cure cerebral glioma. Prognostic factors for survival are histopathologic classification and grading, age, and patient performance. Technological improvements do not improve survival, but possibly reduce late effects.

Purpose: To evaluate prognostic factors in patients with glioblastoma treated with postoperative or primary radiotherapy., Patients and Methods: From 1989 to 2000, a total of 100 patients underwent irradiation as part of their initial treatment for glioblastoma. All patients had undergone surgery or biopsy followed by conventional external-beam radiotherapy. 85 patients who received the planned dose of irradiation (60 Gy in 30 fractions) were analyzed for the influence of prognostic factors. 73/85 (86%) of patients were given postoperative irradiation, while 12/85 (14%) of patients were primarily treated with radiotherapy after biopsy., Results: The median overall survival was 10.1 months (range, 3.7-49.8 months), the 1- and 2-year survival rates were 41% and 5%, respectively. Univariate analysis revealed age < or = 55 years (p < 0.001), pre-radiotherapy hemoglobin (Hb) level > 12 g/dl (p = 0.009), and pre-radiotherapy dose of dexamethasone < or = 2 mg/day (p = 0.005) to be associated with prolonged survival. At multivariate analysis, younger age (p < 0.001), higher Hb level (p = 0.002), lower dose of dexamethasone (p = 0.026), and a hemispheric tumor location (p = 0.019) were identified as independent prognostic factors for longer survival. The median survival for patients with an Hb level > 12 g/dl was 12.1 months compared to 7.9 months for those with a lower Hb level. Contingency-table statistics showed no significant differences for the two Hb groups in the distribution of other prognostic factors., Conclusion: The results indicate that lower Hb level prior to radiotherapy for glioblastoma can adversely influence prognosis. This finding deserves further evaluation.

Background: Pronounced oxygen deficiency in tumors which might be caused by a diminished oxygen transport capacity of the blood (e.g., in anemia) reduces the efficacy of ionizing radiation. The aim of this study was to analyze whether anemia prevention by recombinant human erythropoietin (rHuEPO) affects the radiosensitivity of human glioblastoma xenografts during fractionated irradiation., Material and Methods: Anemia was induced by total body irradiation (TBI, 2 x 4 Gy) of mice prior to tumor implantation into the subcuts of the hind leg. In one experimental group, the development of anemia was prevented by rHuEPO (750 U/kg s.c.) given three times weekly starting 10 days prior to TBI. 13 days after tumor implantation (tumor volume approx. 40 mm3), fractionated irradiation (4 x 7 Gy, one daily fraction) of the glioblastomas was performed resulting in a growth delay with subsequent regrowth of the tumors., Results: Compared to nonanemic control animals (hemoglobin concentration cHb = 14.7 g/dl), the growth delay in anemic mice (cHb = 9.9 g/dl) was significantly shorter (49 +/- 5 days vs. 79 +/- 4 days to reach four times the initial tumor volume) upon fractionated radiation. The prevention of anemia by rHuEPO treatment (cHb = 13.3 g/dl) resulted in a significantly prolonged growth delay (61 +/- 5 days) compared to the anemia group, even though the growth inhibition found in control animals was not completely achieved., Conclusions: These data indicate that moderate anemia significantly reduces the efficacy of radiotherapy. Prevention of anemia with rHuEPO partially restores the radiosensitivity of xenografted glioblastomas to fractionated irradiation.

Background: Standard treatment in patients with malignant glioma consists of surgery and postoperative radiotherapy. A high early recurrence rate, particularly in glioblastoma, has led to the investigation of additional chemotherapy., Material and Methods: Recent results of radiochemotherapy published in the literature were reviewed with respect to outcome in phase II and III trials. Based on these experiences, aspects of future strategies were discussed., Results: 3 decades of intensive research had, unfortunately, little impact on the overall results. While early prospective studies established adjuvant nitrosoureas, particularly BCNU, as suitable adjuvant to surgery and postoperative radiotherapy, further studies largely concentrated on combined chemotherapeutic protocols, mostly procarbazine, CCNU and vincristine (PCV), which was shown to prolong survival in anaplastic astrocytoma. The recent MRC study, however, showed no effect for adjuvant PCV in grade III and IV malignant glioma. Only in high-grade glioma with an oligodendroglial component, additional chemotherapy may be of a decisive benefit. The introduction of newer drugs such as paclitaxel, temozolomide, or gemcitabine demonstrated no decisive advantage. Different modes of application and sequencing of radiotherapy and chemotherapy are presently actively investigated, but failed to substantially improve outcome., Conclusions: Therefore, search for newer and more effective drugs continues, as well as for "optimal" administration and sequencing, especially from the standpoint of accompanying acute and late toxicity. Finally, recent endeavors focused on basic research such as angiogenesis, migration and invasion, or induction of cell differentiation, but these strategies are still away from broader clinical investigation.

Background: To identify prognostic factors for overall survival in patients with newly diagnosed glioblastoma undergoing radiation therapy., Patients and Methods: From January 1980 to June 2000, we treated 432 consecutive patients with glioblastoma at out institution. 17 patients were excluded from the analysis for various reasons. Mean age of the 415 patients who were included in the study was 59 years (19-81 years), Karnofsky performance status (KPS) was > or = 70 in 280 patients. 343 patients underwent resection, 72 had a biopsy. Various fractionation schemes were used (conventional fractionation, n = 112; hypofractionation, n = 94; accelerated hyperfractionation, n = 209). Survival probabilities were estimated using the method of Kaplan and Meier. Multivariate analysis was done with a Cox regression model., Results: By July 2001, 406 patients had died. Medial overall survival was 8.2 months. Of ten factors considered in a proportional hazards model stratified for treatment (fractionation scheme and type of surgery), significant variables in a multivariate model were age (50-64 years vs < 50 years [RR 1.35; 95% CI 1.02-1.78], > or = 65 years vs < 50 years [RR 2.08; 95% CI 1.54-2.81]), performance status (KPS < 70 vs > or = 70 [RR 1.53; 95% CI 1.23-1.90]), and central tumor location (yes vs no [RR 1.39; 95% CI 1.04-1.87]). Blood hemoglobin (Hb) values were available in 318 patients and serum lactate dehydrogenase (LDH) levels in 234 patients. 89 patients were anemic (Hb men < 13 g/dl, women < 12 g/dl), in 80 patients the LDH level was raised beyond the upper limit of the normal range (> 240 U/l). By including the three significant variables, both parameters had an additional significant effect with an estimated relative risk of about 1.4 in their corresponding subgroups., Conclusion: Besides established prognostic factors, anemia and raised serum LDH levels may negatively influence outcome in glioblastoma patients. Our results from data-dependent modeling have to be confirmed by independent studies.