Maximal cardiopulmonary exercise testing in glioblastoma patients undergoing chemotherapy: assessment of feasibility, safety, and physical fitness status.

PURPOSE: Maximal cardiopulmonary exercise testing (max. CPET) provides the most accurate measurement of cardiorespiratory fitness. However, glioblastoma (GBM) patients often undergo less intensive tests, e.g., 6-min walk test or self-rating scales. This study aims to demonstrate feasibility and safety of max. CPET in GBM patients, concurrently evaluating their physical fitness status. METHODS: Newly diagnosed GBM patients undergoing adjuvant chemotherapy were offered participation in an exercise program. At baseline, max. CPET assessed cardiorespiratory fitness including peak oxygen consumption (VO2peak), peak workload, and physical work capacity (PWC) at 75% of age-adjusted maximal heart rate (HR). Criteria for peak workload were predefined based on threshold values in HR, respiratory quotient, respiratory equivalent, lactate, and rate of perceived effort. Data were compared to normative values. Adverse events were categorized according to standardized international criteria. Further, self-reported exercise data pre- and post-diagnosis were gathered. RESULTS: All 36 patients (median-aged 60; 21 men) met the predefined criteria for peak workload. Mean absolute VO2peak was 1750 ± 529 ml/min, peak workload averaged 130 ± 43 W, and mean PWC was 0.99 ± 0.38 W/kg BW, all clinically meaningful lower than age- and sex-predicted normative values (87%, 79%, 90%, resp.). Only once (3%) a minor, transient side effect occurred (post-test dizziness, no intervention needed). Self-reported exercise decreased from 15.8 MET-h/week pre-diagnosis to 7.2 MET-h/week post-diagnosis. CONCLUSION: Max. CPET in this well-defined population proved feasible and safe. GBM patients exhibit reduced cardiorespiratory fitness, indicating the need for tailored exercise to enhance health and quality of life. CPET could be essential in establishing precise exercise guidelines.

Sarcopenia is associated with chemoradiotherapy discontinuation and reduced progression-free survival in glioblastoma patients.

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

Conceptual development of an intensive exercise program for glioma patients (ActiNO): summary of clinical experience.

PURPOSE: Exercise proved to reduce cancer-related symptoms and prolong survival in some cancer types. However, brain tumor patients are often advised against strenuous exercise. Here, we summarize our experience with a submaximal exercise program for glioma patients: ActiNO (Active in Neuro-Oncology). METHODS: Glioma patients were invited to participate in the program. Since 2011, a sports scientist individualized two one-hour sessions per week adapted to the patients' symptoms. One session consisted of bicycle ergometry (average workload: 75% of maximum heart rate), the other of whole-body resistance training. Both sessions were further complimented by coordinative elements. Cardiorespiratory fitness was assessed using the "Physical Work Capacity" procedure. Patients were followed up regularly to assess adherence to the program and disease activity. RESULTS: Until December 2019, 45 glioma patients, median-aged 49 years (IQR 42-59), were included in the analysis. Most patients suffered from glioblastoma (58%), followed by diffuse lower-grade astrocytoma (29%). In overall 1828 training sessions, two minor epileptic events occurred (1 speech arrest; 1 focal seizure). During fitness assessment, all patients achieved at least 75% of their age-adjusted maximum heart rate. Peak workload averaged 172 W (95% CI 156-187). Median survival of participating glioblastoma patients was 24.1 months (95% CI 8.6-39.5). CONCLUSION: This supervised training program with submaximal exertion was feasible and safe in glioma regardless of WHO grading. Based on these experiences, we initiated a prospective multicenter study to objectify improvements in physical performance and quality of life in patients with glioblastoma.

Cervical body composition on radiotherapy planning computed tomography scans predicts overall survival in glioblastoma patients.

Background and purpose: Glioblastoma (GBM) patients face a strongly unfavorable prognosis despite multimodal therapy regimens. However, individualized mortality prediction remains imprecise. Harnessing routine radiation planning cranial computed tomography (CT) scans, we assessed cervical body composition measures as novel biomarkers for overall survival (OS) in GBM patients. Materials and methods: We performed threshold-based semi-automated quantification of muscle and subcutaneous fat cross-sectional area (CSA) at the levels of the first and second cervical vertebral body. First, we tested this method's validity by correlating cervical measures to established abdominal body composition in an open-source whole-body CT cohort. We then identified consecutive patients undergoing radiation planning for recent GBM diagnosis at our institution from 2010 to 2020 and quantified cervical body composition on radiation planning CT scans. Finally, we performed univariable and multivariable time-to-event analyses, adjusting for age, sex, body mass index, comorbidities, performance status, extent of surgical resection, extent of tumor at diagnosis, and MGMT methylation. Results: Cervical body composition measurements were well-correlated with established abdominal markers (Spearman's rho greater than 0.68 in all cases). Subsequently, we included 324 GBM patients in our study cohort (median age 63 years, 60.8% male). 293 (90.4%) patients died during follow-up. Median survival time was 13 months. Patients with below-average muscle CSA or above-average fat CSA demonstrated shorter survival. In multivariable analyses, continuous cervical muscle measurements remained independently associated with OS. Conclusion: This exploratory study establishes novel cervical body composition measures routinely available on cranial radiation planning CT scans and confirms their association with OS in patients diagnosed with GBM.

Digital participation of brain tumour patients in the assessment and treatment of communication disorders.

Introduction: Communication deficits have a severe impact on our social interactions and health-related quality of life. Subtle communication deficits are frequently overlooked or neglected in brain tumour patients, due to insufficient diagnostics. Digital tools may represent a valuable adjunct to the conventional assessment or therapy setting but might not be readily suitable for every patient. Methods: This article summarises results of three surveys on the readiness for telemedicine among (a) patients diagnosed with high-grade glioma, (b) matched controls, and (c) speech and language therapists. The respective surveys assessed the motivation for participation in telemedical assessments and supposed influencing factors, and the use potential of digital assessment and therapy technologies in daily routine, with a spotlight on brain tumour patients and the future prospects of respective telemedical interventions. Respondents included 56 high-grade glioma patients (age median: 59 years; 48% males), 73 propensity-score matched neurologically healthy controls who were instructed to imagine themselves with a severe disease, and 23 speech and language therapists (61% <35 years; all females). Results and discussion: The vast majority of the interviewed high-grade glioma (HGG) patients was open to digitisation, felt well-equipped and sufficiently skilled. The factorial analysis showed that digital offers would be of particular interest for patients in reduced general health condition (p = 0.03) and those who live far from specialised treatment services (p = 0.03). The particular motivation of these subgroups seemed to outweigh the effects of age, equipment and internet skills, which were only significant in the control cohort. The therapists' survey demonstrated a broad consensus on the need for improving the therapy access of brain tumour patients (64%) and strengthening their respective digital participation (78%), although digitisation seems to have yet hardly entered the therapists' daily practise. In summary, the combined results of the surveys call for a joint effort to enhance the prerequisites for digital participation of patients with neurogenic communication disorders, particularly in the context of heavily burdened HGG patients with limited mobility.

Assessment Practice of Patient-Centered Outcomes in Surgical Neuro-Oncology: Survey-Based Recommendations for Clinical Routine.

The psycho-oncological burden related to the diagnosis of an intracranial tumor is often accompanied by neurocognitive deficits and changes in character, overall affecting health-related quality of life (HRQoL) and activities of daily living. Regular administration of adequate screening tools is crucial to ensure a timely detection of needs for support and/or specific interventions. Although efforts have been made to assure the quality of neuro-oncological care, clinical assessment practice of patient-reported outcomes (PROs) remains overall heterogeneous, calling for a concise recommendation tailored to neuro-oncological patients. Therefore, this survey, promoted by the German Society of Neurosurgery, was conducted to evaluate the status quo of health care resources and PRO/neurocognition assessment practices throughout departments of surgical neuro-oncology in Germany. 72/127 (57%) of registered departments participated in the study, including 83% of all university hospital units. A second aim was to shed light on the impact of quality assurance strategies (i.e., department certification as part of an integrative neuro-oncology cancer center; CNOC) on the assessment practice, controlled for interacting structural factors, i.e., university hospital status (UH) and caseload. Despite an overall good to excellent availability of relevant health care structures (psycho-oncologist: 90%, palliative care unit: 97%, neuropsychology: 75%), a small majority of departments practice patient-centered screenings (psycho-oncological burden: 64%, HRQoL: 76%, neurocognition: 58%), however, much less frequently outside the framework of clinical trials. In this context, CNOC affiliation, representing a specific health care quality assurance process, was associated with significantly stronger PRO assessment practices regarding psycho-oncological burden, independent of UH status (common odds ratio=5.0, p=0.03). Nevertheless, PRO/neurocognitive assessment practice was not consistent even across CNOC. The overall most commonly used PRO/neurocognitive assessment tools were the Distress Thermometer (for psycho-oncological burden; 64%), the EORTC QLQ-C30 combined with the EORTC QLQ-BN20 (for HRQoL; 52%) and the Mini-Mental Status Test (for neurocognition; 67%), followed by the Montreal Cognitive Assessment (MoCA; 33%). Accordingly, for routine clinical screening, the authors recommend the Distress Thermometer and the EORTC QLQ-C30 and QLQ-BN20, complemented by the MoCA as a comparatively sensitive yet basic neurocognitive test. This recommendation is intended to encourage more regular, adequate, and standardized routine assessments in neuro-oncological practice.

Quality of Life in Brain Tumor Patients and Their Relatives Heavily Depends on Social Support Factors during the COVID-19 Pandemic.

The COVID-19 pandemic is associated with significant morbidity, mortality, and restrictions on everyday life worldwide. This may be especially challenging for brain tumor patients given increased vulnerability due to their pre-existing condition. Here, we aimed to investigate the quality of life (QoL) in brain tumor patients and relatives in this setting. Over twelve weeks during the first wave of the pandemic (04-07/2020), brain tumor patients and their families from two large German tertiary care centers were asked to complete weekly questionnaires for anxiety, depression, distress, and well-being. Information regarding social support and living conditions was also collected. One hundred participants (63 patients, 37 relatives) completed 729 questionnaires over the course of the study. Compared to relatives, patients showed more depressive symptoms (p < 0.001) and reduced well-being (p = 0.013). While acceptance of lockdown measures decreased over time, QoL remained stable. QoL measures between patients and their families were weakly or moderately correlated. The number of social contacts was strongly associated with QoL. Age, living conditions, ongoing therapy, employment, and physical activity were other predictors. QoL is correlated between patients and their families and heavily depends on social support factors, indicating the need to focus on the entire family and their social situation for QoL interventions during the pandemic.

Feasibility, Safety and Effects of a One-Week, Ski-Based Exercise Intervention in Brain Tumor Patients and Their Relatives: A Pilot Study.

A brain tumor diagnosis poses a significant psychological burden and it severely impacts quality of life (QOL), both in patients and relatives. However, comprehensive strategies addressing QOL in this setting remain rare. Here, we aim to share our findings of a one-week ski exercise intervention, with emphasis on feasibility, safety, QOL, and physical exercise. The intervention consisted of week-long daily ski sessions with professional ski guides as well as dedicated physicians present. The participants were handed questionnaires, including distress and QOL items before, during, and after the intervention. Using fitness watches, exercise intensity was also tracked at these timepoints. During the intervention, patients were checked for adverse events daily. Fifteen participants, nine patients after multidisciplinary treatment, and six relatives were included in the study. Additionally, 13 children participated in the exercise, but not in the study. All of the participants completed the entire program. No severe adverse events were documented during daily checks. There was a strong increase in quantified activity and QOL with a corresponding decrease in distress during the intervention, and, partly, afterwards. This prospective brain tumor rehabilitation study demonstrates the feasibility and safety of challenging ski exercise in brain tumor patients. The findings also underline the exercise-mediated QOL benefits, emphasizing the need for more comprehensive brain tumor rehabilitation programs.

High-Intensity Physical Exercise in a Glioblastoma Patient under Multimodal Treatment.

INTRODUCTION: Glioblastoma multiforme (GBM) carries a strongly unfavorable prognosis despite intensive multidisciplinary therapy. Physical exercise is rarely offered to patients for fear of adverse events such as falls, epileptic seizures, or bleeding, despite little supporting evidence. Here, we report a study of high-level and long-term exercise in a GBM patient. METHODS: A 33-yr-old male, diagnosed with a large cystic GBM, was included in our institution's Personal Training Program after initial tumor resection and adjuvant radiochemotherapy. The program was designed to facilitate individual long-term high-intensity exercise. Supervised by a certified personal trainer, it consisted of at least four weekly training sessions and intermittent performance diagnostics. An activity tracker quantified training intensity. RESULTS: In this setting, the patient exercised at high intensity without adverse events for 87 continuous weeks (21 months). He averaged 43.7 metabolic equivalent of task hours per week (MET·h·wk), well above the 75th percentile of healthy males the same age, while undergoing multiple surgeries, chemotherapy, and radiation therapy regimens. The patient completed two marathons averaging less than 5 min·km both times, despite tumor progression. Performance diagnostics indicated a gain of fitness even during continuous GBM treatment. Due to multiple intraventricular lesions and increasing intracranial pressure, training was stopped 6 wk before the patient passed away 2 yr after initial diagnosis. CONCLUSIONS: This study demonstrates that high-intensity, long-term physical training regimens are feasible in GBM patients during full multidisciplinary therapy. In this patient, the exercise was pursued without adverse events and led to a gain of fitness despite tumor progression and intensive multiple therapies. We conclude that, in GBM patients, exercise regimens require further study instead of general discouragement.

Impact of distress screening algorithm for psycho-oncological needs in neurosurgical patients.

BACKGROUND: Cerebral tumors are associated with high rates of anxiety, depression and reduced health related quality of life. Nevertheless psychooncological screening instruments are neither implemented nor well defined in the daily routine of neurosurgical departments. Therefore, we tried (1) to identify a suitable screening algorithm for neurosurgical patients, (2) to define clinical risk factors for increased distress and (3) to analyze the optimal screening time point. RESULTS: Between October 2013 and January 2015 472 elective neurosurgical in-patients (median age 55.85 years) of the neurosurgical departments of the University Hospitals Duesseldorf and Muenster were prospectively included into this study. Regarding their diagnosis 244 (51.7%) patients were identified with malignant lesions and 228 (48.3%) patients with benign lesions. Increased distress was diagnosed in 63.1% of all patients via DT, in 13.6% via HADS and 27.8% via PO-Bado. Combining the cut-off criteria with the problem list increased sensitivity (90%) and specificity (70%) of the DT assessment. Regarding risk factors pre-existing psychiatric disorders, ataractic medication and a decreased clinical performance status were associated with increased distress. PATIENTS AND METHODS: Patients with diagnosis of an intracranial lesion with elective surgical indication were screened for psychological distress via three assessment-instruments the Hospital Anxiety and Depression Scale (HADS), the Distress Thermometer (DT), and the Basic Documentation for Psycho-Oncology (PO-Bado). Screening results were correlated with clinical and demographic data. CONCLUSION: Postoperative distress screening for neurosurgical patients is important independent from the neurosurgical diagnosis. The DT represents a suitable, non time-consuming instrument for daily routine in a neurosurgical department.

High psychosocial burden in relatives of malignant brain tumor patients.

OBJECTIVE: Not only tumor patients suffer enormously from their disease, also the caregivers are massively affected by the disease of their relatives. In this study, we investigate the psychological burden in caregivers of outpatient malignant brain tumor patients. PATIENTS AND METHODS: Fifty caregivers of patients with primary malignant brain tumors were included in our study. Study participants filled in a form with demographic details, a self-established questionnaire concerning general well-being and three established psychological questionnaires to assess anxiety, depression, stress and social support: The "Hospital Anxiety and Depression Scale" (HADS), the "Perceived Stress Scale" (PSS-10) and the "Social Support Questionnaire" (F-SozU). RESULTS: Caregivers of patients with primary malignant brain tumors showed in the HADS clinically relevant anxiety in 49% and depression in 20% of the cases. The stress level of the caregivers was increased (mean: 18 points) compared to the general population mean: 13 points), although they felt well supported by their social environment (mean: 4.25 points; general population 3.99 points). There was a significant positive correlation between anxiety and depression (p < 0.001). Female caregivers suffered significantly more from anxiety (p = 0.017) and stress (p = 0.012) than their male counterparts. No correlation was found between tumor grade, age of relatives and patients or the state of living together with the patient and anxiety or depression. CONCLUSIONS: Although the caregivers felt well supported by their social environment, stress, anxiety and depression are common phenomena in caregivers of patients with malignant brain tumors. Especially female ones have an increased risk for developing these comorbidities.

Initial psycho-oncological counselling in neuro-oncology: analysis of topics and needs of brain tumour patients.

Diagnosis of a brain tumour is associated with a tremendous disruption of emotional, physical and social well-being. Due to the complexity of the disease and the affection of the central organ, the brain, brain tumour patients differ from other cancer patients. The purpose of this study was to evaluate the concerns and burdens presented by brain tumour patients during their initial psycho-oncological consultation. We performed a retrospective analysis of 53 patients with the diagnosis of either benign or malignant brain tumour, seeking counsel by a neurosurgeon specialised in psycho-oncology. We performed a thematic analysis of the interviews at first consultation identifying themes and patterns and created thematic categories. The main concerns of the patients presented during the first consultations were psychological problems, reported by 40 patients (75.5%). Death and dying was mentioned by more than half of the patients (n = 30, 56.6%). In addition, 62.3% of the patients (n = 33) asked for information regarding the medical treatment and diagnosis. With our study, we created greater awareness of the psychological needs of brain tumour patients in order to define treatment strategies for this important aspect of disease. We showed that there is a need for patients to talk about death even during the initial consultation. Psycho-oncologist in a neuro-oncological setting should be prepared for topics like that and should have a neurosurgical background or collaborate with members of the surgical team in order to provide the patients with medical details and to better understand the impact of the disease.

Erratum to: Gliomatosis cerebri: no evidence for a separate brain tumor entity.

Erratum to: Acta Neuropathol DOI 10.1007/s00401­015­1495­z. The original version of this article contained errors in the alignment of several entries in Tables 4 and 5. The corrected Tables 4 and 5 are given below. The original article has been updated accordingly.

Gliomatosis cerebri: no evidence for a separate brain tumor entity.

Gliomatosis cerebri (GC) is presently considered a distinct astrocytic glioma entity according to the WHO classification for CNS tumors. It is characterized by widespread, typically bilateral infiltration of the brain involving three or more lobes. Genetic studies of GC have to date been restricted to the analysis of individual glioma-associated genes, which revealed mutations in the isocitrate dehydrogenase 1 (IDH1) and tumor protein p53 (TP53) genes in subsets of patients. Here, we report on a genome-wide analysis of DNA methylation and copy number aberrations in 25 GC patients. Results were compared with those obtained for 105 patients with various types of conventional, i.e., non-GC gliomas including diffuse astrocytic gliomas, oligodendrogliomas and glioblastomas. In addition, we assessed the prognostic role of methylation profiles and recurrent DNA copy number aberrations in GC patients. Our data reveal that the methylation profiles in 23 of the 25 GC tumors corresponded to either IDH mutant astrocytoma (n = 6), IDH mutant and 1p/19q codeleted oligodendroglioma (n = 5), or IDH wild-type glioblastoma including various molecular subgroups, i.e., H3F3A-G34 mutant (n = 1), receptor tyrosine kinase 1 (RTK1, n = 4), receptor tyrosine kinase 2 (classic) (RTK2, n = 2) or mesenchymal (n = 5) glioblastoma groups. Two tumors showed methylation profiles of normal brain tissue due to low tumor cell content. While histological grading (WHO grade IV vs. WHO grade II and III) was not prognostic, the molecular classification as classic/RTK2 or mesenchymal glioblastoma was associated with worse overall survival. Multivariate Cox regression analysis revealed MGMT promoter methylation as a positive prognostic factor. Taken together, DNA-based large-scale molecular profiling indicates that GC comprises a genetically and epigenetically heterogeneous group of diffuse gliomas that carry DNA methylation and copy number profiles closely matching the common molecularly defined glioma entities. These data support the removal of GC as a distinct glioma entity in the upcoming revision of the WHO classification.

Predicting the "usefulness" of 5-ALA-derived tumor fluorescence for fluorescence-guided resections in pediatric brain tumors: a European survey.

BACKGROUND: Five-aminolevulinic acid (Gliolan, medac, Wedel, Germany, 5-ALA) is approved for fluorescence-guided resections of adult malignant gliomas. Case reports indicate that 5-ALA can be used for children, yet no prospective study has been conducted as of yet. As a basis for a study, we conducted a survey among certified European Gliolan users to collect data on their experiences with children. METHODS: Information on patient characteristics, MRI characteristics of tumors, histology, fluorescence qualities, and outcomes were requested. Surgeons were further asked to indicate whether fluorescence was "useful", i.e., leading to changes in surgical strategy or identification of residual tumor. Recursive partitioning analysis (RPA) was used for defining cohorts with high or low likelihoods for useful fluorescence. RESULTS: Data on 78 patients <18 years of age were submitted by 20 centers. Fluorescence was found useful in 12 of 14 glioblastomas (85 %), four of five anaplastic astrocytomas (60 %), and eight of ten ependymomas grades II and III (80 %). Fluorescence was found inconsistently useful in PNETs (three of seven; 43 %), gangliogliomas (two of five; 40 %), medulloblastomas (two of eight, 25 %) and pilocytic astrocytomas (two of 13; 15 %). RPA of pre-operative factors showed tumors with supratentorial location, strong contrast enhancement and first operation to have a likelihood of useful fluorescence of 64.3 %, as opposed to infratentorial tumors with first surgery (23.1 %). CONCLUSIONS: Our survey demonstrates 5-ALA as being used in pediatric brain tumors. 5-ALA may be especially useful for contrast-enhancing supratentorial tumors. These data indicate controlled studies to be necessary and also provide a basis for planning such a study.

[Burden and need for psychosocial intervention of glioblastoma patients]. / Belastung und psychosoziale Betreuungsbedürftigkeit von Glioblastompatienten.

Glioblastoma patients should be provided with a professional health care system that helps reduce their psychosocial burden. The aim of this study was to identify patients in need of psychosocial intervention. In addition, it was examined whether physicians' assessments adequately address the burden patients are under and their need for intervention. During their visit to one of two neurosurgery outpatient departments, n = 49 glioblastoma patients filled out the short version of the Hornheider questionnaire (HFK). Consulting physicians also rated their patients' burdens in a specially adapted version of the questionnaire (HFK-F). The results of the psychometric evaluation with both instruments were satisfactory. The majority of the patients (76 %) were identified as in need of psychosocial intervention. All of them were correctly categorized with the physicians' ratings. Physicians overestimated some aspects of the patients' burden, particularly in regard to their problems with relaxing and fear of living with the illness. The patients' ratings concerning the quality of the information physicians provided and their overall state of health only corresponded with the physicians' ratings in roughly half of the cases.

NOA-05 phase 2 trial of procarbazine and lomustine therapy in gliomatosis cerebri.

OBJECTIVE: The NOA-05 multicenter trial was performed to analyze the efficacy of primary chemotherapy with procarbazine and lomustine (PC) in patients with gliomatosis cerebri (GC) and to define clinical, imaging, and molecular factors influencing outcome. METHODS: Thirty-five patients with previously untreated GC were treated with up to six 56-day courses of 110mg/m(2) lomustine on day 1 and 60mg/m(2) procarbazine on days 8 to 21. The primary endpoint was the rate of patients without therapy failure (defined as progressive disease, death from any cause, or termination of PC therapy before the end of course 4) at 8 months after the beginning of PC chemotherapy. RESULTS: The failure-free survival rate at 8 months was 50.3%. Median progression-free survival was 14 months. At progression, 12 patients received salvage radiotherapy. Median overall survival was 30 months. Multivariate analysis revealed isocitrate dehydrogenase 1 (IDH1) gene mutation (hazard ratio [HR], 0.11; 95% confidence interval [CI], 0.02-0.58) and initial presentation without a bilateral symmetrical infiltration pattern on magnetic resonance imaging (HR 0.07, 95%CI 0.01-0.54) as independent prognostic factors associated with prolonged survival. IDH1 mutation was significantly associated with MGMT promoter methylation and an oligodendroglial tumor component. INTERPRETATION: PC chemotherapy is effective in GC. With the NOA-05 trial being the first prospective multicenter trial in GC, PC chemotherapy can be regarded as a promising option for the primary therapy of these tumors.

MGMT activity, promoter methylation and immunohistochemistry of pretreatment and recurrent malignant gliomas: a comparative study on astrocytoma and glioblastoma.

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) is a key player in tumor cell resistance. Promoter methylation, MGMT activity and immunohistochemistry are used for determining the MGMT status. However, it is unclear whether MGMT promoter methylation correlates with MGMT activity and whether MGMT promoter methylation of the pretreatment tumor predicts the MGMT status of recurrences. To address these questions, we determined MGMT activity promoter methylation and immunoreactivity in pretreatment and recurrent glioblastomas (GB, WHO Grade IV), and in astrocytomas (WHO Grade III). We show that GB that were promoter methylated display a range of 0-62 fmol/mg MGMT and tumors that were nonmethylated 0-423 fmol/mg protein. For astrocytomas, promoter-methylated samples displayed 0-28 fmol/mg and, nonmethylated samples, 23-107 fmol/mg. No correlation was found between the intensity of promoter methylation and MGMT activity. Given a threshold level of 30 fmol/mg of protein, we found a correlation between promoter methylation and no/low MGMT activity in 82.4% of the tumors. This high correlation level was only observed when tumors were excluded showing a hemimethylated promoter (20%). Therefore, classification of hemimethylated tumors remains questionable. Further, we show that 39.1% of pretreatment GB and 5.3% of recurrences were promoter methylated, which is in line with the observed increase of MGMT activity in recurrences. Although individual exceptions were found, the data show an overall correlation between promoter methylation and lack/low MGMT activity in GB and astrocytomas. We also show that promoter methylation assay is superior over immunohistochemistry in determining the MGMT status defined by a given MGMT activity level.

Chemoradiotherapy of newly diagnosed glioblastoma with intensified temozolomide.

PURPOSE: To evaluate the toxicity and efficacy of chemoradiotherapy with temozolomide (TMZ) administered in an intensified 1-week on/1-week off schedule plus indomethacin in patients with newly diagnosed glioblastoma. PATIENTS AND METHODS: A total of 41 adult patients (median Karnofsky performance status, 90%; median age, 56 years) were treated with preirradiation TMZ at 150 mg/m(2) (1 week on/1 week off), involved-field radiotherapy combined with concomitant low-dose TMZ (50 mg/m(2)), maintenance TMZ starting at 150 mg/m(2) using a 1-week on/1-week off schedule, plus maintenance indomethacin (25 mg twice daily). RESULTS: The median follow-up interval was 21.7 months. Grade 4 hematologic toxicity was observed in 15 patients (36.6%). Treatment-related nonhematologic Grade 4-5 toxicity was reported for 2 patients (4.9%). The median progression-free survival was 7.6 months (95% confidence interval, 6.2-10.4). The 1-year survival rate was 73.2% (95% confidence interval, 56.8-84.2%). The presence of O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was associated with significantly superior progression-free survival. CONCLUSION: The dose-dense regimen of TMZ administered in a 1-week on/1-week off schedule resulted in acceptable nonhematologic toxicity. Compared with data from the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981-22981/CE.3, patients with an unmethylated MGMT gene promoter appeared not to benefit from intensifying the TMZ schedule regarding the median progression-free survival and overall survival. In contrast, data are promising for patients with a methylated MGMT promoter.