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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.

Purpose: L-[methyl-(11)C]methionine (MET)-positron emission tomography (PET) has a high sensitivity and specificity for imaging of gliomas and metastatic brain tumors. The short half-life of (11)C (20 minutes) limits the use of MET-PET to institutions with onsite cyclotron. O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) is labeled with (18)F (half-life, 120 minutes) and could be used much more broadly. This study compares the uptake of FET and MET in gliomas and metastases, as well as treatment-induced changes. Furthermore, it evaluates the gross tumor volume (GTV) of gliomas defined on PET and magnetic resonance imaging (MRI)., Methods and Materials: We examined 42 patients with pretreated gliomas (29 patients) or brain metastases (13 patients) prospectively by FET- and MET-PET on the same day. Uptake of FET and MET was quantified by standardized uptake values. Imaging contrast was assessed by calculating lesion-to-gray matter ratios. Tumor extension was quantified by contouring GTV in 17 patients with brain gliomas. Gross tumor volume on PET was compared with GTV on MRI. Sensitivity and specificity of MET- and FET-PET for differentiation of viable tumor from benign changes were evaluated by comparing the PET result with histology or clinical follow-up., Results: There was a strong linear correlation between standardized uptake values calculated for both tracers in cortex and lesions: r = 0.78 (p = 0.001) and r = 0.84 (p < 0.001), respectively. Image contrast was similar for MET- and FET-PET (lesion-to-gray matter ratios of 2.36 ± 1.01 and 2.33 ± 0.77, respectively). Mean GTV in 17 glioma patients was not significantly different on MET- and FET-PET. Both MET- and FET-PET delineated tumor tissue outside of MRI changes. Both tracers provided differentiated tumor tissue and treatment-related changes with a sensitivity of 91% at a specificity of 100%., Conclusions: O-(2-[(18)F]fluoroethyl)-L-tyrosine-PET and MET-PET provide comparable diagnostic information on gliomas and brain metastases. Like MET-PET, FET-PET can be used for differentiation of residual or recurrent tumor from treatment-related changes/pseudoprogression, as well as for delineation of gliomas., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Aims: To evaluate models predicting short survival in patients with brain metastases treated with whole-brain radiotherapy (WBRT)., Materials and Methods: This was a retrospective analysis of 312 patients. Each patient was assigned to three different four-tiered prognostic scores: the Basic Score for Brain Metastases (BSBM), the Graded Prognostic Assessment (GPA) and the score developed by Rades et al. In addition, a 'triple-negative' cohort was evaluated (all three scores predicted unfavourable prognosis, n=30)., Results: No statistically significant survival differences were found between the most unfavourable BSBM, GPA, Rades et al. and 'triple-negative' groups. The BSBM best predicted short survival: patients classified in the unfavourable group (Karnofsky performance status <80, uncontrolled primary tumour and presence of extracranial metastases) had a 12.5% survival at 4 months and a 0% 1-year survival. Patients in this group who survived for 4 months or more had simultaneously detected cancer and brain metastases, were treatment naive, and received systemic therapy in addition to WBRT. Excluding this type of patient from the analysis resulted in survival figures that were indistinguishable from those obtained with best supportive care without WBRT in other studies., Conclusions: Although continuous research is necessary to identify patients who can be managed safely and palliated without WBRT, we feel that a model of the BSBM unfavourable group (Karnofsky performance status <80, uncontrolled primary tumour and presence of extracranial metastases) and no intent to treat systemically might form a basis for validation in other large databases. The triple-negativity criterion was not superior for predicting poor prognosis., (Copyright (c) 2009 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Prognostic scores might be useful tools both in clinical practice and clinical trials, where they can be used as stratification parameter. The available scores for patients with brain metastases have never been tested specifically in patients with primary breast cancer. It is therefore unknown which score is most appropriate for these patients., Methods: Five previously published prognostic scores were evaluated in a group of 83 patients with brain metastases from breast cancer. All patients had been treated with whole-brain radiotherapy with or without radiosurgery or surgical resection. In addition, it was tested whether the parameters that form the basis of these scores actually have a prognostic impact in this biologically distinct group of brain metastases patients., Results: The scores that performed best were the recursive partitioning analysis (RPA) classes and the score index for radiosurgery (SIR). However, disagreement between the parameters that form the basis of these scores and those that determine survival in the present group of patients and many reported data from the literature on brain metastases from breast cancer was found. With the four statistically significant prognostic factors identified here, a 3-tiered score can be created that performs slightly better than RPA and SIR. In addition, a 4-tiered score is also possible, which performs better than the three previous 4-tiered scores, incl. graded prognostic assessment (GPA) score and basic score for brain metastases (BSBM)., Conclusion: A variety of prognostic models describe the survival of patients with brain metastases from breast cancer to a more or less satisfactory degree. However, the standard brain metastases scores might not fully appreciate the unique biology and time course of this disease, e.g., compared to lung cancer. It appears possible that inclusion of emerging prognostic factors will improve the results and allow for development and validation of a consensus score for broad clinical application. The model that is based on the authors own patient group, which is not large enough to fully evaluate a large number of potential prognostic factors, is meant to illustrate this point rather than to provide the definitive score.

Background: The purpose of this study is to evaluate the performance of the new "Graded Prognostic Assessment" (GPA) index, which recently was developed from data in the Radiation Therapy Oncology Group (RTOG) database, in patients with brain metastases treated outside of randomized clinical trials., Material and Methods: The authors analyzed 232 patients with brain metastases and assigned these patients to the four indices previously evaluated by the RTOG (recursive partitioning analysis class, Score Index for Radiosurgery, Basic Score for Brain Metastases, and GPA)., Results: The present data confirm the results of the RTOG analysis. Each of the four indices splits the data set into prognostically different groups. In the GPA groups, median survival was 10.3, 5.6, 3.5, and 1.9 months, respectively (p<0.01). In the RTOG analysis, these figures were 11.0, 6.9, 3.8, and 2.6 months, respectively., Conclusion: These results confirm the validity of the GPA index in a patient population that most likely is more representative of the normal clinical situation than patients included in randomized trials.

The purpose of this study was to evaluate the performance of the new Graded Prognostic Assessment (GPA) index, which was recently developed from data in the Radiation Therapy Oncology Group (RTOG) database, in patients treated with surgical resection of brain metastases and postoperative whole-brain radiotherapy. The authors analyzed 64 patients and assigned each patient to each of the four indices previously evaluated by the RTOG (recursive partitioning analysis class, Score Index for Radiosurgery, Basic Score for Brain Metastases and GPA). The present data confirm the validity of the scoring systems in surgically treated patients. Each of the four indices splits the dataset into prognostically different groups; in the GPA groups, median survival was 18.9, 9.8, 5.5, and 3.7 months, respectively (p<0.05). In conclusion, these results confirm the validity of the GPA index in a patient population that previously has not been assessed with this new tool.

Aims: Current prognostic models are not accurate enough to identify brain metastases patients with very short survival, i.e. <2 months, who are unlikely to derive major benefit from whole brain radiotherapy. Our aim was to develop a more reliable model., Materials and Methods: This was a retrospective analysis of a German database, which was used to develop a score, and an additional database from Norway, which was used for validation purposes., Results: The groups included 67 and 32 patients, respectively. An analysis of prognostic factors resulted in a risk score based on performance status, extra-cranial metastases, the interval from breast cancer to brain metastases and a need for corticosteroid treatment, which classified 63 of 67 test patients correctly. However, the validation failed and unfortunately the risk score that performed best in the Norwegian patients (31 of 32 correctly predicted) was not applicable to the German patients., Conclusions: The prediction of short survival is associated with several caveats and seems to result in an unacceptable risk of withholding radiotherapy in patients who actually survive for longer than 2 months.

Background: While elderly patients with brain metastases from lung cancer appear to have an unfavorable prognosis, little information is available on disease presentation and treatment outcome in very young patients., Patients and Methods: Retrospective evaluation of radiation therapy in this particular subpopulation. The database with 149 lung cancer patients contained 9 patients aged <40 years. The majority received whole-brain radiation therapy with 30 Gy in 10 fractions plus steroids, with or without other local or systemic measures according to the institutional policy., Results: Five patients had small-cell histology. Median Karnofsky performance score was 70. In 6 cases, brain metastases were present already at first diagnosis. Eight patients had multiple lesions. Of 8 patients with complete follow-up, only 1 died from spread to the central nervous system (CNS), all others from extracranial disease. Maximum survival was 26 months (median 7 months)., Conclusion: Very young patients with brain metastases did not achieve a better outcome than intermediate age groups. Radiation therapy was able to provide durable CNS control in nearly all patients, while systemic failures remained the leading cause of death. Prospective studies on treatment intensification and quality of life in these patients appear warranted., ((c) 2008 S. Karger AG, Basel.)

Background and Purpose: The extent of treatment in patients with single brain metastasis is a controversial topic. Especially the issue of whole-brain radiotherapy (WBRT) after local treatment of the lesion is largely unresolved. Therefore, the authors performed a pooled analysis of all available clinical data, based on a comprehensive literature search and on prospectively defined inclusion criteria and endpoints (in particular local brain control at the original site and development of new brain metastases)., Material and Methods: Overall, 643 patients from ten publications met the inclusion criteria. 106 patients were treated with surgery alone, 66 with surgery plus local radiotherapy, and the others with surgery plus WBRT (Table 1)., Results: Both types of additional radiotherapy significantly improved local control at the original site (relative risk of local failure <0.5). WBRT also reduced new lesions significantly (relative risk 0.6). Within the available range of doses, no significant dose-response relationship was observed (Figure 1). Even after WBRT, new lesions remained the predominant type of brain failure. One of the underlying causes might be continuous reseeding of cells from active extracranial sites. Toxicity and quality of life were not well described in the publications., Conclusion: The present data favor moderate-dose WBRT, but the pros and cons of each option should be discussed with each patient. Higher radiation doses or local boost treatment are not supported by these data, but might be considered under certain circumstances, e.g., after incomplete resection.

Aim: The purpose of this prospective evaluation was to assess the late neurologic adverse events and Karnofsky performance status (KPS) in patients with at least two brain metastases from non-small cell lung cancer treated with whole-brain radiotherapy (WBRT) with or without sequential systemic chemotherapy., Patients and Methods: All patients were required to have an initial KPS of at least 70%. During the first six months, the patients were re-examined every four weeks, later every 3 months or whenever the clinical condition worsened. Due to slow accrual, the protocol was closed prematurely in 2005. Sixteen adult patients (median age 56 years) treated with 10x3 Gy were studied., Results: Late adverse events > or = grade 2 (CTC AE v3.0) in imaging-confirmed absence of progressive brain metastases developed in 3 patients after a median of 5 months. With a median overall survival of 7 months, the actuarial risk of late adverse events at that time was 0% after WBRT alone and 37% after WBRT and chemotherapy. Thus, larger studies assessing the impact of multimodal treatment are recommended.

Objective: The outcome of whole-brain radiotherapy in elderly patients with brain metastases is not well documented. As the number of such patients is expected to increase, we evaluated our results., Methods: Seventeen patients aged 75-82 years were identified for this retrospective analysis. The majority received 30 Gy in 10 fractions plus steroids (without other local or systemic measures). The median Karnofsky performance score (KPS) was 70., Results: Symptomatic improvement was observed in 53%. Median survival of the responding patients was 4.5 months. However, median survival of the non-responding patients was 1.4 months only. All patients that survived for more than 4 months had a KPS > or =70 and metachronous brain metastases. None of the patients with KPS <70 survived for more than 2.2 months. None of the patients developed severe acute toxicity. One patient developed severe late neurotoxicity., Conclusions: Most elderly patients with brain metastases have an unfavourable prognosis. However, as in other populations, assessment of KPS and few other factors might guide the choice of treatment. Radiation therapy might lead to symptomatic responses in approximately half of the patients, but long-term survivors appear at risk of neurotoxicity. As promising results were published from a retrospective radiosurgery series, prospective trials appear warranted., ((c) 2008 S. Karger AG, Basel)

Despite of postoperative radiotherapy plus temozolomide for newly diagnosed glioblastoma multiforme (GBM) and improvements in the molecular characterization of high-grade glioma, these tumors continue to relapse. We reviewed all clinical studies of re-treatment published between May 2000 and September 2005. In groups of highly selected patients with re-treatment for GBM, median survival reaches 26-27 months. Re-treatment was stereotactic radiotherapy (mostly with additional chemotherapy) or re-resection plus either photodynamic treatment, radioimmunotherapy and temozolomide, or systemic and local chemotherapy. Thus, intense local treatment was always a component of more successful strategies. Additional data suggest that chemotherapy is more efficacious when minimal residual disease is present, although the recent trials have not uncovered a clear regimen of choice. Early trials of immunotherapy and toxin-delivery demonstrate the feasibility of these approaches and encouraging median survival times. Response to erlotinib was more common if tumors had epidermal growth factor receptor gene amplification, protein overexpression and low levels of phosphorylated PKB/Akt. Individual tailoring of such strategies based on molecular profiling is hoped to improve the outcome.

Patients with brain metastases represent a heterogeneous group where selection of the most appropriate treatment depends on many patient- and disease-related factors. Eventually, a considerable proportion of patients are treated with palliative approaches such as whole-brain radiotherapy. Whole-brain radiotherapy in combination with chemotherapy has recently gained increasing attention and is hoped to augment the palliative effect of whole-brain radiotherapy alone and to extend survival in certain subsets of patients with controlled extracranial disease and good performance status. The randomized trials of whole-brain radiotherapy vs. whole-brain radiotherapy plus chemotherapy suggest that this concept deserves further study, although they failed to improve survival. However, survival might not be the most relevant endpoint in a condition, where most patients die from extracranial progression. Sometimes, the question arises whether patients with newly detected brain metastases and the indication for systemic treatment of extracranial disease can undergo standard systemic chemotherapy with the option of deferred rather than immediate radiotherapy to the brain. The literature contains numerous small reports on this issue, mainly in malignant melanoma, breast cancer, lung cancer and ovarian cancer, but very few sufficiently powered randomized trials. With chemotherapy alone, response rates were mostly in the order of 20-40%. The choice of chemotherapy regimen is often complicated by previous systemic treatment and takes into account the activity of the drugs in extracranial metastatic disease. Because the blood-brain barrier is partially disrupted in most macroscopic metastases, systemically administered agents can gain access to such tumor sites. Our systematic literature review suggests that both chemotherapy and radiochemotherapy for newly diagnosed brain metastases need further critical evaluation before standard clinical implementation. A potential chemotherapy indication might exist as palliative option for patients who have progressive disease after radiotherapy.

Purpose: To examine retrospectively the maximum dose to the large skull base/intracranial arteries in fractionated stereotactic radiotherapy (FSRT) and intensity-modulated radiotherapy (IMRT), because of the potential risk of perfusion disturbances., Methods and Materials: Overall, 56 patients with tumors adjacent to at least one major artery were analyzed. Our strategy was to perform FSRT with these criteria: 1.8 Gy per fraction, planning target volume (PTV) enclosed by the 95% isodose, maximum dose 107%. Dose limits were applied to established organs at risk, but not the vessels. If FSRT planning failed to meet any of these criteria, IMRT was planned with the same objectives., Results: In 31 patients (median PTV, 23 cm3), the FSRT plan fulfilled all criteria. No artery received a dose > or =105%. Twenty-five patients (median PTV, 39 cm3) needed IMRT planning. In 11 of 25 patients (median PTV, 85 cm3), no plan satisfying all our criteria could be calculated. Only in this group, moderately increased maximum vessel doses were observed (106-110%, n = 7, median PTV, 121 cm3). The median PTV dose gradient was 29% (significantly different from the 14 patients with satisfactory IMRT plans). Three of the four patients in this group had paranasal sinus tumors., Conclusion: The doses to the major arteries should be calculated in IMRT planning for critical tumor locations if a dose gradient >13% within the PTV can not be avoided because the PTV is large or includes air cavities.

Purpose: Using magnetic resonance imaging (MRI), residual tumor cannot be differentiated from nonspecific postoperative changes in operated patients with brain gliomas. The higher specificity and sensitivity of L-(methyl-11C)-labeled methionine positron emissions tomography (MET-PET) in gliomas has been demonstrated in previous studies and is the rationale for the integration of this investigation in gross tumor volume delineation. The goal of this trial was to quantify the affect of MET-PET vs. with MRI in gross tumor volume definition for radiotherapy planning of high-grade gliomas., Methods and Materials: The trial included 39 patients with resected malignant gliomas. MRI and MET-PET data were coregistered based on mutual information. The residual tumor volume on MET-PET and the volume of tissue abnormalities on T1-weighted MRI (gadolinium [Gd] enhancement) and T2-weighted MRI (hyperintensity areas) were compared using MET-PET/MRI fusion images., Results: The MET-PET vs. Gd-enhanced T1-weighted MRI analysis was performed on 39 patients. In 5 patients (13%), MET uptake corresponded exactly with Gd enhancement, and in 29 (74%) of 39 patients, the region of MET uptake was larger than that of the Gd enhancement. In 27 (69%) of the 39 patients, the Gd enhancement area extended beyond the MET enhancement. MET uptake was detected up to 45 mm beyond the Gd enhancement. MET-PET vs. T2-weighted MRI was investigated in 18 patients. MET uptake did not correspond exactly with the hyperintensity areas on T2-weighted MRI in any patient. In 9 (50%) of 18 patients, MET uptake extended beyond the hyperintensity area on the T2-weighted MRI, and in 18 (100%), at least some hyperintensity on the T2-weighted MRI was located outside the MET enhancement area. MET uptake was detected up to 40 mm beyond the hyperintensity area on T2-weighted MRI., Conclusion: In operated patients with brain gliomas, the size and location of residual MET uptake differs considerably from abnormalities found on postoperative MRI. Because postoperative changes cannot be differentiated from residual tumor by MRI, MET-PET, with a greater specificity for tumor tissue, can help to outline the gross tumor volume with greater accuracy.

A 67-year-old patient with metastatic renal cell cancer was treated with fractionated stereotactic radiotherapy to a hemorrhagic pons metastasis. He then developed multiple cystic brain lesions, suggestive of diffuse metastatic spread. However, further work-up revealed abscesses from bronchopneumonia. Diagnostic and therapeutic aspects as well as potential pitfalls in the management of patients with brain metastases are discussed.

Progress in the biological and molecular characterization of gliomas and studies of factors associated with tumor growth and progression have led to translational research projects and the development of rational new approaches regarding prognostic models, better prediction of response to treatment and innovative therapeutic strategies. This review summarizes the available data on established and emerging prognostic factors and prognostic scores, and discusses their limitations as well as their potential influence on future therapeutic efforts. Recent developments in standard treatment options (i.e., surgery, radiotherapy and chemotherapy) are reviewed. Experimental data indicate that inhibition of several signaling pathways (e.g., epidermal growth factor, transforming growth factor-beta and phosphatidylinositol 3 kinase) may represent a promising therapeutic strategy. Some inhibitory agents (i.e., drugs, antibodies and antisense oligonucleotides) have now entered clinical trials, mainly for recurrent gliomas and a small number are being tested in combination with radiotherapy. Early results of such approaches are presented.

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.

As in female patients, the clinical course in male patients with breast cancer is determined mainly by tumor stage. The literature contains very limited data on either the occurrence or the treatment of CNS metastases. This paper presents the case report of a 69-year-old man with multiple brain metastases 7 years after a diagnosis of lymph-node positive breast cancer, which had earlier already spread to the bones and liver. Whole-brain irradiation with a total dose of 30Gy resulted in palliation of symptoms. Nevertheless, survival was very short (7 weeks from diagnosis). Patients with metastatic breast cancer are at risk for the development of brain metastases. When performance status is poor the survival of patients with brain metastases is very limited. Treatment recommendations are the same as those for female patients with brain metastases from breast cancer.

Purpose: (a) To implement a fully automatic method to integrate (11)C-methionine positron emission tomography (MET-PET) data into stereotactic radiation treatment planning using the commercially available BrainLAB System, by means of CT/MET-PET image fusion. (b) To validate the fully automatic CT/MET-PET image fusion technique with respect to accuracy and robustness. (c) To give a short glance at the clinical consequences for patients with brain tumors., Methods and Materials: In 12 patients with brain tumors (9 meningeomas, 3 gliomas), CT, MRI, and MET-PET were performed for stereotactic fractionated radiation treatment planning. The CT and MET-PET investigations were performed using a relocatable mask for head fixation. Fifteen external reference markers (5 on each lateral and 5 on the frontal localizer plate) that could be identified in CT and MET-PET were applied on the stereotactic localizer frame; the marker positions were exactly defined for both investigations. The MRI/CT fusion was done completely automatically. The CT/MET-PET fusion was performed using two different methods: The gold standard was the CT/PET fusion based on the reference markers, and the test method was the automatic, intensity-based CT/PET fusion, independent of the external markers. The markers visible on CT and transmission PET were matched using a point-to-line matching algorithm. To quantify the amount of misregistration, the two fusion methods were compared by calculating the mean value of deviation between corresponding points inside a cubic volume of interest of > or =512 cm(3) defined within the cranial cavity. The gross tumor volume (CT/MRI) outlined on CT and T1-MRI with contrast medium was compared with the gross tumor volume (PET) defined in the reoriented MET-PET data sets. The clinical impact of MET-PET in tumor volume definition for stereotactic radiotherapy will be discussed., Results: The fully automatic integration of MET-PET into stereotactic radiation treatment planning was successfully realized in all patients investigated. Mean deviation of the intensity-based automatic CT/PET fusion compared with the external marker-based gold standard was 2.4 mm; the standard deviation was 0.5. The algorithm's robustness was evaluated, and the discrepancy of fusion results due to different initial image alignments was determined to be below 1 mm inside the test volume of interest. In patients with meningiomas and gliomas, MET-PET was shown to deliver additional information concerning tumor extension., Conclusion: The precision of the automatic CT/PET image fusion was high. A mean deviation of 2.4 mm is acceptable, considering that it is approximately equal to the pixel size of the PET data sets. MET-PET improves target volume definition for stereotactic fractionated radiotherapy of meningiomas and gliomas.

Background: We evaluated prognostic factors for survival in patients with four or more brain metastases in order to determine whether intense local treatment might be justified for some of them. If up to three brain metastases are present, surgical resection or radiosurgery are currently being considered in case of favorable prognostic factors., Patients and Methods: Retrospective intention-to-treat analysis of 113 patients who underwent whole-brain radiotherapy without surgical resection or radiosurgery at a single institution. Standard treatment was given with ten fractions of 3 Gy. Higher total doses were administered in 13% of patients. Recursive partitioning analysis (RPA) prognostic classes have been described by the Radiation Therapy Oncology Group (RTOG) in 1997 (class I: Karnofsky performance status [KPS] > or = 70%, age < or = 65 years, no extracranial metastases, controlled primary tumor; class III: KPS < 70%; class II: others)., Results: Median number of brain metastases was six (four to 50). Most patients (69%) had extracranial metastases as well. Criteria of RPA Class I (II) were met in 4% (41%), whereas 56% had KPS < 70% and thus were grouped into class III (Tables 1 and 2). Complete or partial remission of brain metastases was found in 46% of patients who underwent computed tomography. Median survival was 4 months, 1-years survival rate 15%. Only age was a borderline significant prognostic factor in univariate analysis (< or = 50 years vs > 50 years, p = 0.05). Strong trends were found for KPS, extracranial metastases, control of the primary tumor, and breast primary tumor. Number of brain metastases, RPA class and treatment-related factors such as total dose or remission of brain metastases had no appreciable influence on survival (Figure 1). Multivariate analysis failed to identify any significant prognostic factor., Conclusions: Patients with four or more brain metastases seem to represent a group with unfavorable prognosis where remission of brain metastases or administration of more than 30 Gy were not associated with increased survival. The number of patients in RPA class I was too small to draw final conclusions. However, there was absolutely no survival difference between patients in class II (median survival 3.6 months) and III (median 4.2 months).

Purpose: Using MRI, residual tumor cannot be differentiated from nonspecific postoperative changes in patients with brain gliomas after surgical resection. The goal of this study was to analyze the value of 123I-alpha-methyl-tyrosine-single photon emission CT (IMT-SPECT) in radiotherapy planning of patients with brain gliomas after surgical resection., Methods and Materials: In 66 patients with surgically resected brain gliomas (33 glioblastomas, 20 anaplastic astrocytomas, 7 anaplastic oligodendrogliomas, and 6 low-grade astrocytomas), IMT-SPECT and MRI were performed for radiotherapy planning. On the MRI/IMT-SPECT fusion images, the volume with IMT uptake was compared with the volume of the hyperintensity areas of T(2)-weighted MRI and with the volume of contrast enhancement on T(1)-weighted MRI. The regions with IMT uptake and/or MRI changes (composite Vol-MRI/IMT), regions with overlay of IMT uptake and MRI changes (common Vol-MRI/IMT), area with IMT uptake without MRI changes (increase Vol-MRI/IMT), and area with only MRI changes (Vol-MRI minus IMT) were analyzed separately. The planning target volume and boost volume defined using MRI information alone was compared with the planning target volume and boost volume defined by also using the SPECT information., Results: Focally increased IMT uptake was observed in 25 (38%) of 66 patients, contrast enhancement on MRI was outlined in 59 (89%) of 66 patients, and hyperintensity areas on T(2)-weighted MRI were found in all 66 investigated patients. The mean composite Vol-T(2)/IMT was 73 cm(3). The relative increase Vol-T(2)/IMT, mean relative common Vol-T(2)/IMT, and mean relative Vol-T(2) minus IMT was 4%, 6%, and 90% of the composite Vol-T(2)/IMT, respectively. The mean composite Vol-T(1)/IMT was 14 cm(3) and the mean relative increase Vol-T(1)/IMT, mean relative common Vol-T(1)/IMT, and mean relative Vol-T(1) minus IMT was 21%, 4%, and 64% of the mean composite Vol-T(1)/IMT, respectively. In 19 (29%) of 66 patients, the focal IMT uptake was located outside the MRI changes. In this subgroup, the mean residual volume defined by focal IMT uptake in MRI/IMT-SPECT images, mean Vol-T(1), and mean Vol-T(2) was 19 cm(3), 10 cm(3), and 70 cm(3), respectively. The mean relative increase T(2)/IMT was 14% and T(1)/IMT was 61%. In this subgroup, the additional information of SPECT led to an increase in boost volume (mean relative increase BV-IMT) by 20%., Conclusion: In patients with surgically resected brain gliomas, the size and location of residual IMT uptake differs considerably from the abnormalities found on postoperative MRI. Because of the known high specificity of IMT uptake for tumor tissue, the findings on IMT-SPECT may significantly modify the target volumes for radiotherapy planning. This will help to focus the high irradiation dose on the tumor area and to spare normal brain tissue.

Unlabelled: The aim of the study was to analyze the results of stereotactic radiotherapy using a linear accelerator in patients with brain metastases. We quantified the following clinical parameters: tumor response and tumor control after therapy, survival, and side effects. Results of the treatment were compared with those from traditional treatment strategies such as surgery and whole brain irradiation. Sixty patients with brain metastases (80 lesions, 36 men and 24 women, mean age 57 years) were treated with stereotactic radiotherapy. The mean follow-up time was 13 months., Conclusion: Stereotactic radiotherapy is an important option in the treatment strategy for patients with brain metastases. In comparison to whole brain irradiation, stereotactic radiotherapy achieved a higher local tumor control with a lower rate of side effects. In comparison to surgery, stereotactic radiotherapy has the advantages of shorter treatment time and lower treatment-related morbidity and mortality.

Unlabelled: The aim of this study was to evaluate the prognostic value of SPECT imaging using the amino acid analog 3-[(123)I]iodo-L-alpha-methyltyrosine (IMT) in patients with gliomas., Methods: One hundred fourteen consecutive patients with newly diagnosed gliomas were examined by IMT SPECT (low-grade glioma, n = 12; anaplastic astrocytoma or oligodendroglioma, n = 46; glioblastoma, n = 56). Seventy-one of these patients had undergone tumor resection 4-6 wk before SPECT imaging (group A). Forty-three patients with unresectable tumors were examined after stereotactic biopsy (group B). IMT uptake at the site of the tumor was assessed visually and quantified relative to a contralateral reference region (IMT uptake ratio). After IMT SPECT, all patients were treated with conformal radiotherapy. The median follow-up time was 27 mo., Results: In group A, focal IMT uptake at the resection site was visible in 52 of 71 patients (73%). Median survival was only 13 mo in these patients, whereas median survival was reached in patients without focal IMT uptake (P = 0.02). Furthermore, the intensity of IMT uptake significantly correlated with survival: patients with an IMT uptake ratio > 1.7 were at a 4.6 times higher risk of death than were patients with a lower IMT uptake (P < 0.001). The IMT uptake ratio remained a significant prognostic factor when age and grading were included in a multivariate model. In contrast, IMT uptake did not correlate with survival in group B (P = 0.95)., Conclusion: In patients with unresectable high-grade gliomas, IMT uptake appears not to correlate with the biologic aggressiveness of tumor cells. Nevertheless, the clear association between focal IMT uptake after tumor resection and poor survival suggests that IMT is a specific marker for residual tumor tissue. Therefore, IMT SPECT is expected to become a valuable tool for the planning and monitoring of local therapeutic modalities.

Retreatment of malignant gliomas may be performed with palliative intent after careful consideration of the risks and benefits, and with special regards to iatrogenic neurotoxicity and quality of life (QOL). This review compares studies of several retreatment strategies (published between 1987 and 2000) based on the quality of their evidence. Depending on both established prognostic factors and previous treatment, individually tailored retreatment strategies are possible. In all studies that included a multivariate analysis of prognostic factors, performance status was the most important. So far, predictive factors for response, which might facilitate patient selection, have not been unequivocally defined. In terms of QOL, single-agent chemotherapy (temozolomide, nitrosoureas, platinum and taxane derivatives) may offer a better therapeutic ratio than polychemotherapy. For glioblastoma multiforme, progression-free survival and QOL were more favourable after temozolomide than procarbazine (level 1 evidence). The survival of patients after various radiotherapy techniques is broadly similar. However, considerable toxicity is associated with radiosurgery or brachytherapy. Fractionated stereotactic radiotherapy plus radio-sensitizing cytostatic agents has shown promising initial results in small groups of selected patients and awaits further evaluation. Level 2 evidence derived from non-randomized studies does not suggest a substantial prolongation of survival by re-resection as compared with chemotherapy or radiotherapy alone. Level 1 evidence derived from a randomized trial suggests that application of BCNU polymers significantly improves the outcome after re-resection. However, most studies reported median survival in the range of only 25-35 weeks, thereby emphasizing the need for the development and clinical evaluation of new innovative treatment approaches., (Copyright 2000 Harcourt Publishers Ltd.)

O-(2-[18F]Fluoroethyl)-L-tyrosine (FET) is a recently described amino acid analogue that has shown high accumulation in animal tumours. The aim of this study was to compare the uptake of FET with that of L-[methyl-11C]methionine (MET) in patients with suspected primary or recurrent intracerebral tumours. Sixteen consecutive patients with intracerebral lesions were studied on the same day by positron emission tomography (PET) using MET and FET. Uptake of FET and MET was quantified by standardized uptake values. Tracer kinetics for normal brain and intracerebral lesions were compared. On the basis of the MET-PET studies, viable tumour tissue was found in 13 patients. All tumours showed rapid uptake of FET and were visualized with high contrast. Mean uptake of FET for normal grey matter, white matter and tumour tissue was 1.1+/-0.2, 0.8+/-0.2 and 2.7+/-0.8 SUV, respectively. In all three tissues, uptake of MET was slightly higher (1.4+/-0.2, 0.9+/-0.1 and 3.3+/-1.0 SUV; P<0.01). However, contrast between tumour and normal tissues was not significantly different between MET and FET. Uptake of FET in non-neoplastic lesions (1.0+/-0.1 SUV) was significantly lower than in tumour tissue (P = 0.007). For all lesions there was a close correlation (r = 0.98) between MET and FET uptake. In conclusion, in PET studies of human brain tumours, the uptake and image contrast of FET appear to be very similar to those of MET. The specificity of FET for tumour tissue is promising but has to be addressed in a larger series of patients with non-neoplastic lesions.

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

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.

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

Background: High-grade malignant gliomas have a dismal prognosis. Only achievement of long-term local control improves overall survival. Conventional treatments have not been successful, but thermoradiotherapy appears to be a promising new approach to this disease., Patients and Methods: The review addresses the various HT techniques applied for brain heating, the biological rationale and experimental studies supporting the use of heat in addition to radiotherapy for brain tumors. Normal brain damage exposed to heat is critically evaluated. Clinical trials implementing HT for tumors of the brain accumulating more than 400 patients are discussed., Results: HT is a feasible and effective approach to brain tumors. Important selection criteria are tumor size (< 6 cm) and location (supratentorial, peripheral). Acute treatment toxicity is relatively low and long-term side effects are similar to those observed for RT alone. In some studies a high response rate and improvement of survival was achieved. Tumor control and survival depend on histology (anaplastic astrocytoma vs. glioblastoma multiforme), extent of surgery (complete vs. incomplete), tumor status (primary vs. recurrent), age and performance status. Satisfactory heating also correlates significantly with favourable treatment outcome., Conclusions: The encouraging results of clinical trials may be biased by favourable tumor and patient selection. Randomized clinical trials comparing RT alone versus combined RT-HT for advanced and recurrent brain tumors are justified. Part I has covered biological and technical fundamentals of clinical hyperthermia and has been published in Strahlenther. Onkol. 168 (1992), 183-190. Part II has covered clinical fundamentals and results in superficial tumors of clinical hyperthermia and has been published in Strahlenther. Onkol. 169 (1993), 633-654. Part III has covered clinical rationale and results in deep seated tumors and has been published in Strahlenther. Onkol. 171 (1995), 251-264.