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Background: Alopecia causes significant distress for patients and negatively impacts quality of life for low-grade glioma (LGG) patients. We aimed to compare and evaluate variations in dose distribution for scalp-sparing in LGG patients with proton therapy and photon therapy, namely intensity-modulated proton therapy (IMPT), intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and helical tomotherapy (HT)., Methods: This retrospective study utilized a dataset comprising imaging data from 22 patients with LGG who underwent postoperative radiotherapy. Treatment plans were generated for each patient with scalp-optimized (SO) approaches and scalp-non-optimized (SNO) approaches using proton techniques and photons techniques; all plans adhered to the same dose constraint of delivering a total radiation dose of 54.04 Gy to the target volume. All treatment plans were subsequently analyzed., Results: All the plans generated in this study met the dose constraints for the target volume and OARs. The SO plans resulted in reduced maximum scalp dose (D max ), mean scalp dose (D mean ), and volume of the scalp receiving 30 Gy (V 30 ) and 40 Gy (V 40 ) compared with SNO plans in all radiation techniques. Among all radiation techniques, the IMPT plans exhibited superior performance compared to other plans for dose homogeneity as for SO plans. Also, IMPT showed lower values for D mean and D max than all photon radiation techniques., Conclusion: Our study provides evidence that the SO approach is a feasible technique for reducing scalp radiation dose. However, it is imperative to conduct prospective trials to assess the benefits associated with this approach., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: Vitexin can cooperate with hyperbaric oxygen to sensitize the radiotherapy of glioma by inhibiting the hypoxia-inducible factor (HIF)-1α. However, whether vitexin has a direct radiosensitization and how it affects the HIF-1α expression remain unclear. This study investigated these issues., Methods: The SU3 cells-inoculated nude mice were divided into control, radiation, and vitexin + radiation groups. The vitexin + radiation-treated mice were intraperitoneally injected with 75 mg/kg vitexin daily for 21 days. On the 3rd, 10th, and 17th days during the vitexin treatment, the radiation-treated mice were locally irradiated with 10 Gy, respectively. In vitro, the microRNA (miR)-17-5p or miR-130b-3p mimics-transfected SU3 cells were used to examine the effects of vitexin plus radiation on expression of miR-17-5p- or miR-130b-3p-induced radioresistance-related pathway proteins. The effects of vitexin on miR-17-5p and miR-130b-3p expression in SU3 cells were also evaluated., Results: Compared with the radiation group, the tumor volume, tumor weight, and expression of HIF-1α, vascular endothelial growth factor, and glucose transporter-1/3 proteins, miR-17-5p, and miR-130b-3p in tumor tissues in the vitexin + radiation group decreased, whereas the expression of phosphatase and tensin homolog (PTEN) protein increased. After treatment of miR-17-5p or miR-130b-3p mimics-transfected SU3 cells with vitexin plus radiation, the PTEN protein expression also increased, the HIF-1α protein expression decreased correspondingly. Moreover, vitexin decreased the miR-17-5p and miR-130b-3p expression in SU3 cells., Conclusion: Vitexin can enhance the radiosensitivity of glioma, and its mechanism may partly be related to the attenuation of HIF-1α pathway after lowering the inhibitory effect of miR-17-5p and miR-130b-3p on PTEN., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Purpose: Concomitant chemoradiation followed by repeat (dose-deescalated) irradiation has become standard of care in treating childhood diffuse intrinsic pontine glioma (DIPG) during first line treatment and at first progression. Progression after re-irradiation (re-RT) is in most cases symptomatic and either treated systemically with chemotherapy or new innovative approaches including targeted therapy. Alternatively, the patient receives best supportive care. Data on second re-irradiation in DIPG patients with second progression and good performance status are sparse. This is a case report of second short-term re-irradiation to shed further light on this option., Methods: Retrospective case report of a 6-year-old boy with DIPG receiving a second course of re-irradiation (with 21.6 Gy) as part of an individual multimodal approach in a patient with very low symptom burden., Results: The second course of re-irradiation was feasible and well tolerated. No acute neurological symptoms or radiation-induced toxicity occurred. Overall survival was 24 months after initial diagnosis., Conclusion: A second course of re-irradiation can be an additional tool in patients with progressive disease after first- and second-line irradiation. It is unclear whether and to what extent it contributes to progression-free survival prolongation and if-since our patient was asymptomatic-progression-associated neurological deficits can be alleviated., (© 2023. 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: Spinal cord gliomas are rare, and there is no consensus on the optimal radiotherapy (RT) regimen. Herein, we investigated therapeutic outcomes in spinal cord gliomas to obtain clues for the optimal RT regimen., Methods: We assessed 45 patients who received RT for primary spinal cord non-ependymoma gliomas between 2005 and 2017: 37 (82%) received postoperative RT, 6 (13%) underwent definitive RT without surgery, and 2 (5%) received salvage RT for recurrent tumors. Craniospinal irradiation (CSI; median, 40 Gy) was administered in 4 patients with seeding at diagnosis; all other patients received local RT only (median, 50.4 Gy)., Results: In all 23 failures occurred (20 in patients without initial seeding +3 in patients with initial seeding and CSI; median follow-up, 33 months). The 2‑year overall survival and progression-free survival rates were 74 and 54%, respectively. Overall, 13 (32%) new seeding events outside the local RT field developed either first or subsequently. Tumor grade was significantly associated with survival endpoints (p = 0.009, 0.028) and overall seeding rates (p = 0.042). In grade II tumors, seeding developed in 23%, with a dismal prognosis (median, 10 months after RT). In grade III tumors, seeding developed in 45% with diverse prognosis. In grade IV tumors, seeding developed in 45%. The survival of patients with newly developed seeding was significantly worse than the others (2-year 50%, p < 0.001)., Conclusion: To encompass a considerable rate of progressive disease seeding, aggressive treatment such as pre-emptive application of CSI needs to be considered for high-grade spinal cord gliomas with adverse features. Prophylactic CSI could be an option for survival prolongation and requires prospective validation.

Purpose: Paediatric high grade glioma (pHGG) are rare. Following maximum safe resection, children >3 years with HGG receive radiotherapy as standard of care. Whether the interval from tumour surgery to radiotherapy (ISRT) influences survival is disputed in adults with glioblastoma, data for children are lacking. This retrospective single-centre analysis investigates a possible impact of ISRT on survival in paediatric patients with HGG., Methods: Survival was analysed in patients aged 3-19 years with non-pontine HGG., Results: Thirty-eight patients were included (female:male 19:19) with a median age of 11.0 years (3.4-17.7). Seventeen patients had grade 3 and 21 grade 4 glioma. Gross total resection was achieved in 26.3%, partial resection in 36.8% and 36.8% underwent biopsy only. All patients received concomitant and adjuvant chemotherapy. Fifty percent (n = 19) started irradiation ≤17 days (median interval 12 days [range 5-17]), 50% thereafter (median 28 days [range 19-78]). More patients with grade 4 tumours were irradiated shortly after surgery. ISRT (as a continuous variable and dichotomised into two groups by the median ISRT of 18 days) did not significantly influence overall survival (OS) or progression-free survival (PFS). Higher extent of resection (EOR), lower tumour grade as well as chemotherapy with temozolomide had a significant positive impact on OS and PFS in univariate analysis and (except for the effect of temozolomide on PFS) also in multivariable analysis., Conclusions: ISRT did not influence survival in pHGG. In view of upcoming targeted treatment options in pHGG the present data suggest that it is safe to perform molecular analyses within a 4-week timeframe before radiotherapy.

Background and Purpose: Low-grade glioma (LGG) is a very common brain tumor in pediatric patients typically associated with a very good prognosis. This prognosis makes it imperative that the risk of long-term treatment-related side effects be kept at an absolute minimum. Proton therapy (PRT) provides a radiation technique that has the potential to further reduce the genesis of radiogenic impairment., Materials and Methods: We retrospectively assessed 74 patients with LGG who underwent PRT. Conventional three-dimensional photon and PRT plans were generated after contouring structures of neurogenesis, crucial neuronal structures, and areas susceptible to secondary malignancies. Target volume coverage was evaluated using the homogeneity index (HI) and inhomogeneity coefficient (IC). Results were compared using the Wilcoxon-signed rank test, with p < 0.05 being statistically significant., Results: Target volume coverage was comparable for the photon and proton plans. Overall, we could show an essential reduction in maximal, mean, and integral doses in critical neurologic structures, areas of neurogenesis, and structures of neurocognitive function. The study indicated specifically how contralaterally located structures could be spared with PRT., Conclusion: PRT is a highly conformal radiation technique offering superior dosimetric advantages over conventional radiotherapy by allowing significant dose reduction for organs at risk (OAR) that are essential for neurologic function, neurocognition, and quality of life, thus demonstrating the potential of this technique for minimizing long-term sequelae., Competing Interests: Compliance with ethical guidelinesConflict of interestS.B. Harrabi, N. Bougatf, A. Mohr, T. Haberer, K. Herfarth, S.E. Combs, J. Debus, and S. Adeberg state that there are no conflicts of interest.Ethical standardsAll studies on humans described in the present manuscript were carried out with the approval of the responsible ethics committee and in accordance with national law and the Helsinki Declaration of 1975 (in its current, revised form).

Background: Due to the rarity of spinal cord gliomas, no consensus has been reached regarding the optimal treatment strategy. The aim of the present retrospective study was to identify patient and tumor characteristics and to evaluate the effectiveness of radiotherapy within this setting., Patients and Methods: Patients diagnosed with spinal cord gliomas between 2003 and 2013 and treated at the Department of Radiation Oncology, University of Munich, were retrospectively analyzed. Overall survival was estimated with the Kaplan-Meier method and univariate analysis was performed by log-rank testing., Results: A total of 16 patients were identified. The cohort consisted of seven primary spinal cord gliomas and eight cases of metastases of cerebral gliomas. Median follow-up was 42 months and median total radiation dose was 45.0 Gy. In all, 62.5 % of patients received a simultaneous chemotherapy with temozolomide. The median overall survival was 6 months (95% CI: 0-27.5 months). Surgical resection of the tumor was a significant predictor of improved survival, compared with radiotherapy alone (p = 0.001). Patients with the diagnosis of a primary spinal cord glioma survived significantly longer than those presenting with a metastatic deposit from a cerebral glioma (p < 0.001). A statistically significant dose-response relationship at dose levels of ≥ 45 Gy vs. < 45 Gy could be derived (p < 0.001). Simultaneous chemotherapy did not influence survival outcome., Conclusion: Despite the aggressive treatment in the present study, the prognosis for spinal cord gliomas was still poor, with a median overall survival of 6 months. To the best of our knowledge, this is the largest study reporting the results of simultaneous chemoradiation in spinal cord gliomas. A combined chemoradiation treatment seems feasible and can be considered as a new treatment option in the management of spinal cord gliomas.

Purpose: To compare a quasi-volumetric modulated arc therapy (qVMAT) with three-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) for the treatment of high-grade gliomas. The qVMAT technique is a fast method of radiation therapy in which multiple equispaced beams analogous to those in rotation therapy are radiated in succession., Patients and Methods: This study included 12 patients with a planning target volume (PTV) that overlapped at least one organ at risk (OAR). 3D-CRT was planned using 2-3 non-coplanar beams, whereby the field-in-field technique (FIF) was used to divide each field into 1-3 subfields to shield the OAR. The qVMAT strategy was planned with 15 equispaced beams and IMRT was planned using 9 beams with a total of 80 segments. Inverse planning for qVMAT and IMRT was performed by direct machine parameter optimization (DMPO) to deliver a homogenous dose distribution of 60 Gy within the PTV and simultaneously limit the dose received by the OARs to the recommended values. Finally, the effect of introducing a maximum dose objective (max. dose < 54 Gy) for a virtual OAR in the form of a 0.5 cm ring around the PTV was investigated., Results: The qVMAT method gave rise to significantly improved PTV95% and conformity index (CI) values in comparison to 3D-CRT (PTV95% = 90.7 % vs. 82.0 %; CI = 0.79 vs. 0.74, respectively). A further improvement was achieved by IMRT (PTV95% = 94.4 %, CI = 0.78). In qVMAT and IMRT, the addition of a 0.5 cm ring around the PTV produced a significant increase in CI (0.87 and 0.88, respectively), but dosage homogeneity within the PTV was considerably reduced (PTV95% = 88.5 % and 92.3 %, respectively). The time required for qVMAT dose delivery was similar to that required using 3D-CRT., Conclusion: These findings suggest that qVMAT should be preferred to 3D-CRT for the treatment of high-grade gliomas. The qVMAT method could be applied in hospitals, for example, which have limited departmental resources and are not equipped with systems capable of VMAT delivery.

Background and Purpose: Most patients with malignant glioma ultimately fail locally or loco-regionally after the first treatment, with re-irradiation being a reasonable treatment option. However, only limited data are presently available allowing for a precise selection of patients suitable for re-treatment with regard to safety and efficacy., Material and Methods: Using the department database, 39 patients with a second course of radiation were identified. Doses to gross tumor volume (GTV), planning target volume (PTV), and relevant organs at risk (OARs; brainstem, optic chiasm, optic nerves, brain) were retrospectively analyzed and correlated to outcome parameters. Relevant treatment parameters including D(max), D(min), D(mean), and volume (ml) were obtained. Equivalent uniform dose (EUD) values were calculated for the tumor and OARs. To address the issue of radiation necrosis/leukoencephalopathy posttherapeutic MRI images were routinely examined every 3 months., Results: Median follow-up was 147 days. The time interval between first and second irradiation was regularly greater than 6 months. Median EUDs to the OARs were 11.9 Gy (range 0.7-27.4 Gy) to the optic chiasm, 17.6 Gy (range 0.7-43.0 Gy) to the brainstem, 4.9/2.1 Gy (range 0.3-24.5 Gy) to the right/left optic nerve, and 29.4 Gy (range 25.2-32.5 Gy) to the brain. No correlation between treated volume and survival was observed. Cold spots and dose did not correlate with survival. Re-irradiated volumes were treated with on average lower doses if they were larger and vice versa., Conclusion: In general, re-irradiation is a safe and feasible re-treatment option. No relevant toxicity was observed after re-irradiation in our patient cohort during follow-up. In this regard, this analysis provides baseline data for the selection of putative patients. EUD values are derived and may serve as reference for further studies, including intensity-modulated radiotherapy (IMRT) protocols.

Purpose: To assess survival, local control and toxicity using fractionated stereotactic conformal radiotherapy (FSCRT) boost and temozolomide in high-grade gliomas (HGGs)., Patients and Methods: Patients affected by HGG, with a CTV(1)(clinical target volume, representing tumor bed ± residual tumor + a margin of 5 mm) ≤ 8 cm were enrolled into this phase II study. Radiotherapy (RT, total dose 6,940 cGy) was administered using a combination of two different techniques: three-dimensional conformal radiotherapy (3D-CRT, to achieve a dose of 5,040 or 5,940 cGy) and FSCRT boost (19 or 10 Gy) tailored by CTV(1)diameter (≤ 6 cm and > 6 cm, respectively). Temozolomide (75 mg/m(2)) was administered during the first 2 or 4 weeks of RT. After the end of RT, temozolomide (150-200 mg/m(2)) was administered for at least six cycles. The sample size of 41 patients was assessed by the single proportion-powered analysis., Results: 41 patients (36 with glioblastoma multiforme [GBM] and five with anaplastic astrocytoma [AA]) were enrolled; RTOG neurological toxicities G1-2 and G3 were 12% and 3%, respectively. Two cases of radionecrosis were observed. At a median follow-up of 44 months (range 6-56 months), global and GBM median overall survival (OS) were 30 and 28 months. The 2-year survival rate was significantly better compared to the standard treatment (63% vs. 26.5%; p < 0.00001). Median progression-free survival (PFS) was 11 months, in GBM patients 10 months., Conclusion: FSCRT boost plus temozolomide is well tolerated and seems to increase survival compared to the standard treatment in patients with HGG.

Background and Purpose: Treatment options for recurrent high-grade glioma after a complete course of radiotherapy comprise surgery, reirradiation and chemotherapy but the efficacy of any of the given salvage treatments is limited. In order to further define the role of short-term radiotherapy as retreatment option for selected patients, we analyzed outcomes after treatment with a hypofractionated radiation., Patients and Methods: Treatment outcomes (overall survival and treatment-associated toxicity) were analyzed retrospectively in 31 patients treated between 1994 and 2007. Hypofractionated radiotherapy was performed after three-dimensional CT planning with a median total dose of 20 Gy in a single department., Results: With a median interval of 20 months from primary radiotherapy, two grade III and 29 grade IV tumors were reirradiated. Pretreatment consisted of surgery and involved-field radiotherapy (median 59 Gy). 77% of the patients received additional chemotherapy before the second course of radiotherapy, and 48% were treated after secondary resection. The median overall survival after hypofractionated radiotherapy was 10.2 months, and the median overall survival time after primary diagnosis 30.9 months. No severe toxicity was observed., Conclusion: Hypofractionated reirradiation with 20 Gy given over 1 week is a practicable and well-tolerated treatment option for patients with recurrent malignant glioma. The overall survival was comparable to the reported outcomes from other series including those with longer treatment protocols.

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.

Purpose: To evaluate the impact of positron emission tomography (PET) on target volume delineation for radiation treatment planning., Material and Methods: The data of the literature concerning the use of PET in target volume delineation are summarized. The following points are discussed for each tumor entity: biological background for the PET investigation, sensitivity and specificity of PET (with different tracers) in comparison to computed tomography (CT) and magnetic resonance imaging (MRI) and impact of PET on target volume definition. New PET tracers, which could visualize biological pathways, such as hypoxia, proliferation, angiogenesis, apoptosis and gene expression patterns, will also be discussed., Results: The results of clinical studies on the integration of PET in target volume definition for lung, head-and-neck, genitourinary and brain tumors were analyzed. Fluorodeoxyglucose-(FDG-)PET has a significant impact on GTV (gross tumor volume) and PTV (planning target volume) delineation in lung cancer and can detect lymph node involvement and differentiate malignant tissue from atelectasis. In head-and-neck cancer, the value of FDG-PET for radiation treatment planning is still under investigation. For example, FDG-PET could be superior to CT and MRI in the detection of lymph node metastases and unknown primary cancer and in the differentiation of viable tumor tissue after treatment. Therefore, it might play an important role in GTV definition and sparing of normal tissue. Choline PET and acetate PET are promising tracers in the diagnosis of prostate cancer, but their validity in local tumor demarcation, lymph node diagnosis and detection of recurrence has to be defined in future clinical trials. FDG-PET seems to be particularly valuable in lymph node status definition in cervical cancer. In high-grade gliomas and meningiomas, methionine PET helps to define the GTV and differentiate tumor from normal tissue. For other entities like gastrointestinal cancer, lymphomas, sarcomas, etc., the data of the literature are yet insufficient. The imaging of hypoxia, cell proliferation, angiogenesis, apoptosis and gene expression leads to the identification of different areas of a biologically heterogeneous tumor mass that can individually be targeted using intensity modulated radiotherapy (IMRT). In addition, a biological dose distribution can be generated, the socalled dose painting. However, systematic experimental and clinical trials are necessary to validate this hypothesis., Conclusion: Regarding treatment planning in radiotherapy, PET offers advantages in terms of tumor delineation and the description of biological processes. To define the real impact of this investigation in radiation treatment planning, subsequent experimental, clinical and cost-benefit analyses are required.

Purpose: To evaluate the feasibility, safety and efficacy of daily temozolomide concurrent with postoperative radiotherapy in malignant glioma., Patients and Methods: From 11/1999 to 03/2003, n = 81 patients aged 15-72 years (median 52 years, Karnofsky score 80-100% in 83%) suffering from primary glioblastoma (n = 47), anaplastic astrocytoma (n = 6), anaplastic oligodendroglioma (n = 16), and recurrent glioma (n = 12) were treated. Patients with primary gliomas received a combination of postoperative radiotherapy (60 Gy/1.8- to 2.0-Gy fractions) and daily oral temozolomide (75 mg/m(2)) at all irradiation days (30-33 doses), while recurrent tumors were treated with 45-60 Gy and temozolomide. Initially, 6/81 patients had daily temozolomide doses of 50 mg/m(2)., Results: In total, 70/81 patients (86%) completed both radio- and chemotherapy. Grade 1 nausea/vomiting was seen in 28%, grade 2 in 11%, grade 3 in 1%. Antiemetics were applied in 41%. Hematologic toxicities were observed as follows: leukopenia grade 3/4 1%, lymphopenia grade 3/4 46%, thrombopenia grade 3/4 1%. Two patients under dexamethasone suffered herpes encephalitis after one and 16 doses of temozolomide (75 mg/m(2)). Median survival was 15 months for glioblastoma. In oligodendroglioma patients, a 4-year survival rate of 78% was observed., Conclusion: Postoperative radiochemotherapy with 30-33 daily doses of temozolomide (75 mg/m(2)) is safe in patients with malignant glioma. The combined schedule is effective in oligodendroglioma patients and may prolong survival in glioblastoma. Effort should be taken to minimize corticosteroid doses, since both steroids and temozolomide lead to immunosuppression.

Background: The EORTC Trial 22845 on the role of immediate postoperative radiotherapy in patients with supratentorial lowgrade glioma revealed an advantage of immediate postoperative radiotherapy for progression-free survival, but not for overall survival. It is still an open question in which clinical setting immediate radiotherapy should be considered and whether chemotherapy may become a useful alternative., Material and Methods: Reports in the literature spanning 60 years of radiation therapy were reviewed with respect to timing of radiotherapy, prognostic factors, dose prescriptions, modern treatment techniques, and late effects. Data on chemotherapy were also reviewed. Based on these data, the role of immediate postoperative radiotherapy or chemotherapy in adult low-grade glioma is presented., Results: Radiotherapy is able to control symptoms in up to 80% of cases. Malignant transformation occurs in 36-86% of cases upon progressive disease. Long-term median survival crucially depends on prognostic factors and ranges between 12 months and 10 years. Radiotherapy does not cause neurocognitive deficits, provided that modern treatment techniques and moderate dose prescriptions are used. Recent series with small patient numbers indicate that chemotherapy using PCV or temozolomide may prolong median survival and induces response rates of 50% in oligodendroglial tumors., Conclusion: The arguments for immediate postoperative irradiation include: low-grade gliomas respond to radiotherapy; the tumors often display an aggressive pathobiological behavior; patients with high risk profile may benefit from immediate radiotherapy in terms of progression-free and overall survival; modern focal radiotherapy is far less toxic than feared; radiotherapy might be more effective at diagnosis than at progression. Chemotherapy might be an alternative in immediate postoperative treatment. Its role, however, is unclear. The forthcoming prospective trial of the EORTC will address this issue in a randomized setting.

Background and Purpose: The publication of Radiation Therapy Oncology Group (RTOG) Study 83-02 in 1996 stimulated further investigations of altered fractionation, i. e., application of more than one fraction per day, in high-grade gliomas. This review summarizes the results of trials published between January 1997 and June 2002., Material and Methods: To identify suitable trials, a Medline search was performed by use of the following key words: brain tumors/astrocytoma/glioma/high-grade glioma/malignant glioma/glioblastoma multiforme and accelerated radiotherapy/hyperfractionated radiotherapy/altered fractionation. In addition, the search was extended to reference lists of articles and textbooks. Whenever possible, data were extracted from the original papers on an intention-to-treat basis, i. e., patients with protocol violations were not excluded for the purpose of this analysis. Studies in brain stem gliomas, pediatric patients and studies which achieved acceleration by radiosurgery, stereotactic radiotherapy, or brachytherapy rather than conventional external-beam treatment were not included. An exploratory analysis of 2-year survival was also performed. For this purpose, the 2-year survival rate was extracted from each individual study. The total number of 2-year survivors was then calculated for each treatment strategy and compared by use of the chi(2)-test., Results: The authors identified 1,414 patients from 21 studies; two of these were randomized phase III studies. In seven studies (658 patients), chemotherapy or radiosensitizers were not administered in addition to radiotherapy. The others provide a very heterogeneous set of data, because a large variety of drugs and administration schedules was used. Seven studies included patients with glioblastoma multiforme only, two were limited to patients with anaplastic gliomas. Dose per fraction was 1.2-1.8 Gy in 17 studies and 1.9-2.65 Gy in four. Overall treatment time was 12-31 days, except for one study. Three out of five studies where three fractions per day were administered, included a 2-week break (split-course studies). None of the studies reported a significant improvement in survival by altered fractionation in comparison to either institutional historical controls or their respective randomized control arm. Doses of 60-70 Gy do not appear to improve survival compared to 50-60 Gy. The current data provide no arguments for use of three instead of two fractions per day. Median survival was 10 months after radiotherapy alone (658 patients) and 11 months after combined treatment (756 patients). Regarding 2-year survival rates, radiotherapy alone resulted in 13%, combined chemoradiation or use of sensitizers in 23% (p < 0.0001). However, prognostic factors such as tumor histology were not equally distributed and favor the combined-treatment group. Evaluation of six studies of conventional radiotherapy alone resulted in data from 571 patients. Their median survival was 10.8 months. Cumulative 2-year survival amounted to 15%. The studies of conventional radiotherapy plus chemotherapy or sensitizers included 1,115 patients with a median survival of 11 months (2-year survival rate 18.5%)., Conclusion: Altered fractionation shortens the overall treatment time for adult patients with supratentorial high-grade gliomas. However, there is no significant survival improvement.

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.

Background: For more than 60 years, radiation therapy has been an integral part in the management of childhood low-grade glioma. As this tumor carries an excellent long-term prognosis, the risk of late effects is of particular clinical importance and impinges upon radiotherapeutic treatment strategies., Material and Methods: Studies on the use of radiation therapy in children with low-grade glioma were systematically reviewed for data on radiotherapy-induced side effects on brain parenchyma, endocrine dysfunction, growth retardation, neurocognitive dysfunction, vasculopathy, and secondary neoplasms., Results: Data on late effects are scarce and heterogeneous. Past reports included only retrospective series from the 1930s to present days, a time during which treatment policies and radiation techniques widely varied and considerably changed in recent years. Often, considerable uncertainty existed regarding pretreatment health status and radiotherapy-related factors (e.g., total dose, dose per fraction, treatment fields). In spite of these shortcomings and often conflicting observations, it appears that especially younger children and children with neurofibromatosis (NF) are at risk of endocrinopathies in terms of growth retardation and developmental abnormalities, as well as neurocognitive dysfunction expressed as problems in the psychosocial environment such as in education and occupation. However, both observations may be attributed to the higher proportion of NF in the very young who frequently develop large tumors spreading along the entire supratentorial midline. The risk of radiation-induced disturbances in visual function is low (no case reported). Young children with NF appear to have an increased risk of vasculopathies. 33 cases of moyamoya disease were found (preferably in the very young), 18 of whom were NF-positive. Other cerebrovascular accidents (24 cases, of whom 14 were NF-positive) and secondary neoplasms (15 cases, of whom only five occurred in field--four were high-grade astrocytomas) are a rare condition. The latter cannot be distinguished from late relapses with malignant transformation. Modern treatment techniques appear to reduce the risk of radiation-induced late effects., Conclusions: More studies and clear definitions of clinical endpoints such as neurocognitive and endocrinological outcome are needed in order to clarify the impact of radiation therapy on the risk of late sequelae. Presently, the strategy to postpone radiotherapy in the younger children, especially with NF, is justified to reduce the risk of late effects. These information and the contribution of tumor, surgery and chemotherapy will help to define the role of radiation therapy in the future management of childhood low-grade glioma and whether the use of highly sophisticated and expensive treatment techniques is justifiable. The recently initiated prospective study of the APRO (Pediatric Radiooncology Working Party) on documentation of dose prescription to organs at risk and the network of the GPOH to explore late effects as well as the forthcoming prospective SIOP/GPOH (International Society of Pediatric Oncology/German Society of Pediatric Oncology and Hematology) LGG 2003 trial are addressing these issues.

Background: Treatment of childhood low-grade gliomas is a challenging issue owing to their low incidence and the lack of consensus about "optimal" treatment approach., Material and Methods: Reports in the literature spanning 60 years of radiation therapy, including orthovoltage, megavoltage and recently modern high-precision treatments, were reviewed with respect to visual function, survival, prognostic factors, dose prescriptions, target volumes, and treatment techniques. Based on these experiences, future strategies in the management of childhood low-grade glioma are presented., Results: Evaluation of published reports is difficult because of inconsistencies in data presentation, relatively short follow-up in some series and failure to present findings and results in a comparable way. Even with the shortcomings of the reports available in the literature, primarily concerning indications, age at treatment, dose response, timing and use of "optimal" treatment fields, radiation therapy continues to play an important role in the management of these tumors achieving long-term survival rates up to 80% or more. Particularly in gliomas of the visual pathway, high local tumor control and improved or stable visual function is achieved in approximately 90% of cases. Data on dose-response relationships recommend dose prescriptions between 45 and 54 Gy with standard fractionation. There is consensus now to employ radiation therapy in older children in case of progressive disease only, regardless of tumor location and histologic subtype. In younger children, the role of radiotherapy is unclear. Recent advances in treatment techniques, such as 3-D treatment planning and various "high-precision" treatments achieved promising initial outcome, however with limited patient numbers and short follow-ups., Conclusions: Radiation therapy is an effective treatment modality in children with low-grade glioma regarding tumor control and improvement and/or preservation of neurologic function or vision, respectively. More prospective studies are needed to address the impact of modern radiation therapy technologies (including intensity-modulated radiotherapy) on outcome especially in the very young and to define the role of radiation therapy as a part of a comprehensive treatment approach. The forthcoming prospective trial SIOP/GPOH LGG RT 2003 is addressing this issue.

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.

Aim: Determination of in-vitro radiosensitivity and genetic alterations of cell cultures derived from human glioma biopsy tissue and established glioma cell lines., Material and Methods: Fresh brain tumor specimens of six patients were processed to early passage cell cultures. In addition the cell lines D 384 and Gli 6 were used. Cell cultures were irradiated with doses from 2 to 10 Gy. Following irradiation, cell survival was determined by clonogenic assay and survival curves were generated. The surviving fractions after 2 Gy (SF2) and 4 Gy (SF4) were used as radiosensitivity parameters. Genetic analysis included determination of the mutational and loss of heterozygosity (LOH) status of TP 53 (exons 5-8), the LOH 10- and epidermal growth factor receptor gene (EGFR) amplification status., Results: The SF2 and SF4 values ranged from 0.54 to 0.88 (mean: 0.70) and from 0.13 to 0.52 (mean: 0.32), respectively. Genetic alterations were found in the Gli 6 cell line and in two primary cell cultures. The genetic profile of Gli 6 showed LOH but no TP 53 mutation, complete LOH 10 and no EGFR amplification. The VU 15 cell culture showed TP 53 mutation but no LOH 10 or EGFR amplification, while VU 24 showed incomplete LOH 10, EGFR amplification and no TP 53 mutation. In the other four cell cultures and D 384 cell line no genetic alterations were diagnosed. Histopathological classification of glioblastoma multiforme and/or genetic alterations resulted in lower radiosensitivity., Conclusion: In this small series of early passage glioma cell cultures low radiosensitivity and alterations in cell regulatory genes were seen. Further testing of biological behavior in larger series of patient-derived material is ongoing.

Background: Paclitaxel is a radiosensitizing agent that shows a synergistic effect with radiation in malignant glioma cells. A phase I/II trial was performed in order to evaluate both feasibility and outcome of combined radiochemotherapy in malignant glioma., Patients and Methods: 56 patients were included in the trial. Paclitaxel was administered on days 1-4, 15-18 and 29-32 18 to 24 hours prior to irradiation. Radiotherapy with 60 Gy in conventional fractionation was initiated on day 2.31 patients were included in a dose-escalation trial starting with 20 mg/m2/d and increasing up to 60 mg/m2/d in 10-mg steps. Additional 25 patients were treated with 50 mg/m2/d., Results: The regimen was very well tolerated with minimal subjective impairment such as sickness or weakness. Maximal tolerable dose was 50 mg/m2/d, with neutropenia being the dose-limiting toxicity. There were four allergic reactions and five thromboembolisms; furthermore, one patient with a normal blood count died due to pneumonia. The median survival was 12 months, and significantly favorable factors were a young age, a lower tumor grade (grade 3) and a complete resection. Varying the paclitaxel dose had no influence on outcome., Conclusions: Combined radiochemotherapy with paclitaxel in the treatment of malignant glioma was well tolerated. Maximal tolerable dose was 50 mg/m2/d. There was no increase in survival compared with results reported in the literature.

Purpose: Analysis of the feasibility and effect of hyperbaric oxygen treatment (HBO) on cognitive functioning in patients with cognitive disorders after irradiation of the brain., Patients and Method: Seven patients with cognitive impairment after brain irradiation, with an interval of at least 1.5 years after treatment, were treated with 30 sessions of HBO in a phase I-II study. A comprehensive neuropsychological test battery was performed before treatment, at 3 and 6 months thereafter. Patients were randomized into an immediate treatment group and a delayed treatment group. The delayed group had a second neuropsychological test at 3 months without treatment in that period and started HBO thereafter., Results: All eligible patients completed the HBO treatment and the extensive neuropsychological testing. One out of seven patients had a meaningful improvement in neuropsychological functioning. At 3 months there was a small, but not significant benefit in neuropsychological performance for the group with HBO compared to the group without HBO treatment. Six out of seven patients eventually showed improvement after HBO in one to nine (median 2.5) of the 31 tests, although without statistical significance., Conclusion: HBO treatment was feasible and resulted in a meaningful improvement of cognitive functioning in one out of seven patients. Overall there was a small but not significant improvement.

Background: This retrospective study was undertaken to analyze the patterns of failure in patients with malignant glioma after localized irradiation., Patients and Materials: Recurrence patterns of 46 patients with malignant glioma (glioblastoma: 24, anaplastic astrocytoma: 15, anaplastic oligodendroglioma: 5, unclassified malignant glioma: 2) were studied using CT/MR scans and radiotherapy plan-plots. All patients were operated before and a total dose of 5,940 cGy was given after CT assisted and individually configurated 3-D planning using 7-15 slices at an in between distance of 5 mm. The target volume included a 2-3 cm margin beyond the tumor indicated by preoperative CT scan. The following parameters were analyzed: tumor size and type, size of perifocal edema and whether the edema was fully included into treatment volume and finally the location of the recurrent tumor. The maximal distance between primary tumor and recurrent tumor was measured and also the distance from the border of the primary tumor to the distant border of edema for a visual analysis., Results: Local limited volume irradiation was sufficient since 73.9% of recurrences occurred within 2 cm distance from primary tumor and 93.5% of recurrences occurred completely within 3 cm distance from primary tumor. Regarding the distance between primary tumor and recurrent tumor and the time interval until appearance of recurrent tumor it was not of importance if perifocal edema was included completely into treatment volume or not., Conclusion: Limited volume irradiation of malignant glioma with a target volume 3 cm beyond that indicated by preoperative CT scan seems to be sufficient, since 93.5% of recurrences were completely within 3 cm distance from the margin of the tumor. Improvement of the results with larger treatment volumes are unlikely. Complete irradiation of perifocal edema was not found to be necessary.

Purpose: Dedicated mask systems nowadays allow the use of stereotactic radiotherapy in fractionated regimes, therefore combining the advantages of high precision radiotherapy with the biological benefit of fractionation. Therefore the knowledge of institution specific isocenter accuracy is essential for decision-making about margins to be allowed to form the planning target volume., Patients and Method: Measurements of isocenter deviations during fractionated treatments were performed in 33 patients using the simulator Simulix-xy (Oldelft) in connection with the BrainLab angiographic localizer-box as well as port-films. In both cases repeated images were overlaid by use of anatomical landmarks with a methodical accuracy in the order of 0.5 mm., Results: Both methods yield random isocenter deviations of less then 2 mm (standard deviation) in all three directions and no significant systematic deviations. These values are in the order of the accuracy of the method, obtained by comparison of two independent investigators, as well as they are comparable with the literature., Conclusions: The accuracy of less than 2 mm indicates safety margins of 3-4 mm as sufficient for clinical routine to cover the target in 95.5% of all set-ups (2 SD).

Purpose: Neuropsychological impairment has been reported following whole brain and partial brain irradiation in children. The purpose of this analysis was to assess current knowledge, with focus on correlation with radiation dose, irradiated volume and age., Method: Full Scale IQ (FSIQ) data, representing 1,938 children, were derived from 36 publications and analyzed as to radiation dose, irradiated volume, and age., Results: FSIQ after whole brain irradiation showed a non-linear decline as dosage increased. The dose-effect relationship was age-related, with more pronounced FSIQ decline at younger age. FSIQ test results below the normal level (< 85) were found at doses higher than 24 and 36 Gy in children under age 3, and older than age 6, respectively. Mean FSIQ test result after 18 Gy was 100, thus at the mean standard value; a minor decline was detectable only when compared to test results of a control group. Young children scored at this dose in the low normal range. Partial brain irradiation caused minor FSIQ decline, with measurable effects at dose levels > 50 Gy., Conclusion: The collected data suggest that whole brain irradiation doses of 18 and 24 Gy have no major impact on intellectual outcome in children older than age 6, but may cause impairment in younger children. Doses > 24 Gy comprise a substantial risk for FSIQ decline, even in older children. At equal dose levels, partial brain irradiation is less damaging than whole brain irradiation. The authors are well aware of limitations in the interpretation of data collected for the current review. Thus, further research is required to evaluate the effect of low-dose whole brain irradiation as well as partial brain irradiation on FSIQ development.

Background and Purpose: To assess treatment outcome and prognostic factors following postoperative external radiotherapy in 77 patients with low-grade glioma., Patients and Methods: Between 1977 and 1996, 45 patients with astrocytoma, 14 with oligodendroglioma and 18 with mixed glioma received postoperative radiotherapy with a median total dose of 52 Gy (range, 45 to 61 Gy). Sixty-seven patients were treated immediately following surgery, 10 patients with tumor progression. The influence of various factors including histology, gender, age, seizures, duration of symptoms (< or = 6 weeks vs > 6 weeks), CT pattern (enhancement vs no enhancement), type of surgery, total radiotherapy dose and timing of radiotherapy on relapse-free survival and overall survival was investigated., Results: The median overall survival time was 81 months, the 5- and 10-year survival rates were 54% and 31%, respectively. The median time to progression was 56 months, while the 5- and 10-year progression-free survival rates were 45% and 24%. Univariate analyses identified the total radiotherapy dose (p = 0.01), duration of symptoms (p = 0.05), the presence of seizures (p = 0.04), and the CT pattern following intravenous contrast (p = 0.005) as significant prognostic factors for overall survival. Progression-free survival rates were influenced by the total dose (p = 0.04), the duration of symptoms (p = 0.01) and CT pattern (p = 0.006). On multivariate analysis, only the CT pattern (enhancement vs no enhancement) remained as independent prognostic factors for both progression-free survival and overall survival., Conclusions: A minimum total dose of 52 Gy is recommended for the postoperative radiotherapy in low-grade glioma. Tumors with CT enhancement seem to need further intensification of treatment.

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.

Purpose: Patients with malignant gliomas have a limited survival prognosis. We retrospectively analyzed data of malignant glioma patients with the aim of defining prognostic factors on which individualized treatment strategies might be built on., Patients and Methods: Seventy-six patients with primary malignant glioma (51 glioblastoma multiforme, 20 anaplastic astrocytoma, 4 anaplastic oligo-astrocytoma, 1 anaplastic glioma) were postoperatively irradiated with 5 and 8 Me V photons, 2 Gy per fraction to a median total dose of 60 Gy (range 50 to 70 Gy)., Results: The youngest quartile of patients (up to 45 years) had the highest 3-year survival rates (mean +/- SE: 15 +/- 8%) and median survival time (17.9 months, 95% confidence interval: 9.2, 24.2 months) as compared to the oldest quartile (> 61 years) with no 3-year survivor and a median survival time of 9.7 months (7.2, 12.3 months). The middle quartiles (46 to 61 years) showed intermediate results. The difference between the youngest and oldest quartile (p = 0.01) and the middle quartile versus the oldest quartile (p = 0.04) was significant. In univariate analysis, tumor size (p = 0.04 for -30 mm vs > 50 mm) was of importance. In multivariate analysis only age of the patient reached statistical significance (p = 0.03). As compared to the youngest quartile of patients, the oldest quartile had a relative risk of 2.1 (95% confidence interval: 0.9, 5.1) of dying from the disease; the age group of 46 to 61 years had a relative risk of 2.0 (0.9, 4.3)., Conclusions: Age of the patient is the most important factor for survival prognosis favouring younger age (< or = 45 years). The possible implications for radiation therapy are discussed.

Purpose: Feasibility and morbidity of IORT for malignant brain tumors as well as value of innovative imaging for diagnosis of rest tumors and recurrences were examined., Methods and Materials: Between May 1992 and November 1993, 23 patients with malignant brain tumors were treated in Münster with IORT. The patient collective was heterogeneous and negatively selected, i.e. beside of primary treatments, also patients with extensive previous treatment, recurrent tumors or metastases were included. Therapy consisted of radical surgical resection and intraoperative electron radiotherapy using total doses from 15 Gy to 25 Gy relative to the 90% isodose. Afterwards, patients without prior treatment underwent percutaneous irradiation with a maximum dose of 60 Gy, related to the small volume of the tumor area plus a safety margin of 2 cm., Results: No increase of peri-operative morbidity or subacute sequelae was observed. Overall 1-year survival was 67% for grade III gliomas (WHO), and 56% for glioblastoma multiforme. When the Matsutani selection criteria (primary therapy of a supratentorial, peripheral astrocytoma grade III or glioblastoma smaller than 5 cm in diameter with a Karnofsky performance index of more than 60% and possible wide resection) were applied, 1-year survival increased to 75%. Nuclear medical diagnostics using 123I-alpha-methyltyrosin SPECT proved a valuable method for imaging of non-resectable tumor tissue and diagnosis of recurrences., Conclusions: The results of this study indicate that IORT can contribute to successful tumor treatment while neither increasing peri-operative morbidity nor subacute sequelae.

The results of combined radiotherapy with fast neutrons and photons for 39 malignant gliomas were analyzed. The patients consisted of 16 astrocytoma grade 3 and 23 glioblastoma multiforme. There were two kinds of combination methods which were either "boost therapy" or "mixed beam therapy" with a localized fast neutron field. The average dose of fast neutrons was 569 cGy (n, gamma) and that of photons was 36.86 Gy. The median survival of astrocytoma grade 3 was 15.5 months, and that of glioblastoma multiforme was also 15.5 months. With respect to the combination methods, there was no difference between the boost regimen and the mixed beam regimen. This result seems to have no impact on survival compared to other reports. Patients' ages, surgical debulking procedures, and photon doses were listed as significant prognostic factors, but doses of fast neutrons had no prognostic significance for survival. Because there were no moderate or severe complications for the brain except permanent epilation in all cases, neutron dose escalation study with a localized field will be recommended.

A proposed treatment protocol with boron neutron capture therapy using epithermal neutrons is outlined. It is intended for the initial patients with supratentorial malignant gliomas to be irradiated at the High Flux Reactor in Petten, Holland.

An unusual protocol based on a preliminary clinical study on cylindromas metastasized to the lung was proposed to brain glioma patients: Day 2 100 mg/m2 i.v. Cis platinum (Cis PII) followed at days 3 and 5 by 6 Gy irradiation (RT) in two fractions and three days. Five cycles were scheduled at 21 days interval. On disease progression a three fractions per day radiotherapy regimen (3 FRT) in split-course (two series of 22.50 Gy in 15 fractions and five days separated by a two weeks period of rest) was then delivered to the patients. All patients had a measurable mass on the CT scan. 19 were entered into the study: 13 as first line therapy (group A) and six for salvage treatment (group B). Tolerance was globally good. Eight patients were considered responders at the end of five cycles of Cis PII-RT. They were all group A patients. Median symptom-free interval was six months for the whole population. Survival was twelve months. The 3 FRT was well tolerated but does not seem to have improved the therapeutic gain of the chemoradiotherapy combination. The present study concerns patients whose prognosis was poor on inclusion: surgery inadvisable or unsatisfactory and diagnosis mainly based on biopsy only. The number and the duration of responses justify further study into Cis PII as first line therapy as either an effective cytotoxic drug or a potential radio enhancer.

Dose-effect relations have been evaluated by the treatment of cell cultures (9L glioma cells of rat as monolayers and tumor spheroids, L 1210 cells of mice) with activated isophosphamide, adriamycin, epirubicin and 6 MeV electrons. The magnitude of synergistic effects obtained by combined treatment modalities is strictly pH-dependent, but even for tumor spheroids it appears that there exists an optimum time-interval between drug administration and consecutive irradiation. The determination of the intracellular pH value with the help of pH sensor microelectrodes and 31P NMR spectroscopy indicates that 31P spectroscopy only provides the global pH of the complete culture (average value), whereas the local pH can only be determined by sensors. The ATP-concentration before and after irradiation depends significantly on the glucose supply of the culture medium.

The yield of dicentric chromosomes has been recorded in peripheral blood lymphocytes of patients undergoing telecobalt therapy for glioblastoma. Blood samples were taken by venipuncture, prior to the first radiotherapy session and 24 h after 10, 20 and 30 Gy to the tumor volume. On the basis of the maximum likelihood method, the yield of chromosome aberrations was best fitted by a linear quadratic dose-response relationship. According to this relationship, the dose inducing ten dicentrics at the target volume is 58 Gy, a value considerably higher than those found after radiotherapy for mammary carcinoma (15 Gy) or for pelvic tumors (5.62 Gy). Our results indicate that, in the case of fractionated exposures, confined to a small volume of the body, it is not possible to estimate the total dose administered and that the method only provides an estimate of the proportion of the lymphocytes irradiated.

Since 1985, inoperable brain tumors, astrocytoma III or glioblastoma multiforme, have been treated by means of fractionated afterloading therapy combines with subsequent percutaneous irradiation. A screw that was specifically designed, allowed us to fix a precious metal tube to the skull cap for about eight days making possible the application of a marginal tumor dose of 30 Gy at a daily fractionation of 2 X 2 Gy using the iridium-afterloading-technique. Percutaneous saturation with another 30-40 Gy followed. Supported by radiobiological considerations, fractionation also appears to have a favorable influence on the perifocal edema formation in the brachytherapy of malignant brain tumors. After an observation period of four years probabilities of survival amounting to six months and twelve months can be calculated (according to Kaplan-Meier) for 68% and 27% of the total collective, respectively (n = 38). The survival rate for patients without pretreatment (n = 16) was 81% and 41% after six and twelve months respectively.

Two chemically induced rat glioblastomas, RG2 and F98, were cultured as monolayers and as multicellular spheroids and subjected to Co-gamma-irradiation. In parallel, intercellular communication between cells was determined as electrical coupling between neighbouring cells using micro-electrode techniques. A third glioblastoma with known radiobiological response (9L) was assayed with respect to intercellular communication and included into this analysis. Electrical coupling was low for RG2, intermediate for F98, and high for 9L. Radioresistance of spheroids, as expressed in terms of the mean inactivation dose computed from the survival curves increased in the same direction (RG2: 2.4 Gy; F98: 5.1 Gy; 9L: 6.5 Gy). A comparison of these parameters demonstrates a correlation between solid tumor radioresistance and gap-junctional cell-to-cell communication, at least for the class of glioblastomas analysed in this study.

A clinical trial with neutron brachytherapy for malignant glioma is now in progress at the University of Kentucky Medical Center. In the initial three year period, 32 patients entered the study. There were 24 males and eight females, and the peak incidence was seen in the seventh decade. All patients underwent surgical resection of tumor followed by Cf-252 implantation and external radiotherapy. The implantation procedure was well tolerated by the patients and demonstrated a short-term benefit in survival of patients who were able to complete planned radiotherapy. Older patients had less tolerance to radiotherapy. The evaluation of the beneficial effects of Cf-252 brachytherapy will require patients who are able to tolerate the whole course of therapy.

Between 1980 and 1986 ten patients (two males, eight females, median age: 35 years) with spongioblastomas and ependymomas grade I of the spinal cord were treated with fast neutrons from the d(14) + Be reaction after incomplete tumour surgery. Eight patients received three weekly fractions of 0.7 to 1.33 Gy and two patients four weekly fractions of 0.8 Gy to total doses of 7.4 to 10.4 Gy. Two complete and six partial remissions of ataxia and motor disturbances were observed. Bladder dysfunctions in five patients cleared up partially in three cases. In two patients the symptomatology remained unchanged. After a follow-up of eight to 88 months two initially complete and two out of six partial remission were maintained. No severe late effects of the skin have been determined. In summary it is concluded that for incompletely resected "pencil"-gliomas fast neutron therapy seems to be a feasible treatment modality.