Publications by authors named "Brigitta G Baumert"

86 Publications

Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study.

Lancet Oncol 2021 06 14;22(6):813-823. Epub 2021 May 14.

Radiotherapy Department, Gustave Roussy University Hospital, Villejuif, Cedex, France.

Background: The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.

Methods: This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.

Findings: Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.

Interpretation: Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.

Funding: Merck Sharpe & Dohme.
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http://dx.doi.org/10.1016/S1470-2045(21)00090-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191233PMC
June 2021

Immunotherapy and Radiotherapy for Older Cancer Patients during the COVID-19 Era: Proposed Paradigm by the International Geriatric Radiotherapy Group.

Gerontology 2021 Mar 30:1-7. Epub 2021 Mar 30.

Department of Radiation Oncology, University Hospital of Martinique, Martinique, France.

Background: Older cancer patients with locally advanced or metastatic disease may benefit from chemotherapy alone or combined with radiotherapy. However, chemotherapy is often omitted either because of physician bias or because of its underlying comorbidity, thus compromising their survival. The coronavirus disease 19 (COVID-19) pandemic is compounding this issue because of the fear of immunosuppression induced by chemotherapy on the elderly which makes them more vulnerable to the virus.

Summary: Immunotherapy has less effect on the patient bone marrow compared to chemotherapy. The potential synergy between radiotherapy and immunotherapy may improve local control and survival for older patients with selected cancer. Preliminary data are encouraging because of better survival and local control in diseases which are traditionally resistant to radiotherapy and chemotherapy such as melanoma and renal cell carcinoma. Key Message: We propose a new paradigm combining immunotherapy at a reduced dose and/or extended dosing intervals and hypofractionated radiotherapy for older patients with selected cancer which needs to be tested in future clinical trials.
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http://dx.doi.org/10.1159/000514451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8089416PMC
March 2021

Calculating the net clinical benefit in neuro-oncology clinical trials using two methods: quality-adjusted survival effect sizes and joint modeling.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa147. Epub 2020 Oct 29.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Two methods combining survival and health-related quality of life (HRQoL) data in glioma trials to calculate the "net clinical benefit" were evaluated: Quality-adjusted effect sizes (QASES) and joint modeling (JM).

Methods: The net clinical benefit in two trials was calculated as proof of concept for other trials. With the QASES method, effect sizes for differences in progression-free survival (PFS) or overall survival (OS) and HRQoL between the experimental arm and standard treatment arm were calculated, while the relative emphasis placed on survival/HRQoL varied. JM allows simultaneous modeling of HRQoL and OS/PFS.

Results: In the EORTC 26951 trial, combined radiochemotherapy significantly prolonged OS (difference 11.7 months), but also resulted in more patients experiencing clinically relevant worsening (≥10 points) in appetite loss and nausea/vomiting shortly after treatment. Using QASES, the survival benefit of additional procarbazine, lomustine, and vincristine (PCV) decreased from 42.3 months to 29.5 and 28.2 months when accounting for appetite loss and nausea/vomiting, respectively. JM analyses resulted in a loss of the beneficial effect of additional PCV between 13% and 24% when adjusting for different HRQoL parameters. The EORTC 22033 trial showed no significant PFS difference between radiotherapy or temozolomide alone (46 vs 39 months), nor clinically relevant differences in HRQoL. JM analyses also showed no significant association between PFS and HRQoL scales/items, whereas QASES showed that temozolomide alone was more favorable when considering symptom burden (47-49 instead of 39 months).

Conclusions: Both methods resulted in different outcomes, but adjusting for the impact of treatment on HRQoL resulted in theoretically reduced survival benefits.
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http://dx.doi.org/10.1093/noajnl/vdaa147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772555PMC
October 2020

ESTRO ACROP guideline for target volume delineation of skull base tumors.

Radiother Oncol 2021 03 10;156:80-94. Epub 2020 Dec 10.

Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy; IRCCS Neuromed, Pozzilli, Italy. Electronic address:

Background And Purpose: For skull base tumors, target definition is the key to safe high-dose treatments because surrounding normal tissues are very sensitive to radiation. In the present work we established a joint ESTRO ACROP guideline for the target volume definition of skull base tumors.

Material And Methods: A comprehensive literature search was conducted in PubMed using various combinations of the following medical subjects headings (MeSH) and free-text words: "radiation therapy" or "stereotactic radiosurgery" or "proton therapy" or "particle beam therapy" and "skull base neoplasms" "pituitary neoplasms", "meningioma", "craniopharyngioma", "chordoma", "chondrosarcoma", "acoustic neuroma/vestibular schwannoma", "organs at risk", "gross tumor volume", "clinical tumor volume", "planning tumor volume", "target volume", "target delineation", "dose constraints". The ACROP committee identified sixteen European experts in close interaction with the ESTRO clinical committee who analyzed and discussed the body of evidence concerning target delineation.

Results: All experts agree that magnetic resonance (MR) images with high three-dimensional spatial accuracy and tissue-contrast definition, both T2-weighted and volumetric T1-weighted sequences, are required to improve target delineation. In detail, several key issues were identified and discussed: i) radiation techniques and immobilization, ii) imaging techniques and target delineation, and iii) technical aspects of radiation treatments including planning techniques and dose-fractionation schedules. Specific target delineation issues with regard to different skull base tumors, including pituitary adenomas, meningiomas, craniopharyngiomas, acoustic neuromas, chordomas and chondrosarcomas are presented.

Conclusions: This ESTRO ACROP guideline achieved detailed recommendations on target volume definition for skull base tumors, as well as comprehensive advice about imaging modalities and radiation techniques.
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http://dx.doi.org/10.1016/j.radonc.2020.11.014DOI Listing
March 2021

Measuring change in health-related quality of life: the impact of different analytical methods on the interpretation of treatment effects in glioma patients.

Neurooncol Pract 2020 Dec 7;7(6):668-675. Epub 2020 Jun 7.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Different analytical methods may lead to different conclusions about the impact of treatment on health-related quality of life (HRQoL). This study aimed to examine 3 different methods to evaluate change in HRQoL and to study whether these methods result in different conclusions.

Methods: HRQoL data from 15 randomized clinical trials were combined (CODAGLIO project). Change in HRQoL scores, measured with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and BN20 questionnaires, was analyzed in 3 ways: (1) at the group level, comparing mean changes in scale/item scores between treatment arms, (2) at the patient level per scale/item, calculating the percentage of patients that deteriorated, improved, or remained stable per scale/item, and (3) at the individual patient level, combining all scales/items.

Results: Baseline and first follow-up HRQoL data were available for 3727 patients. At the group scale/item level, only the item "hair loss" showed a significant and clinically relevant change (ie, ≥10 points) over time, whereas change scores on the other scales/items were statistically significant only (all  < .001; range in change score, 0.1-6.2). Although a large proportion of patients had stable HRQoL over time (range, 27%-84%) on the patient level per scale/item, many patients deteriorated (range, 6%-43%) or improved (range, 8%-32%) on a specific scale/item. At the individual patient level, the majority of patients (86%) showed both deterioration and improvement, whereas only 1% remained stable on all scales.

Conclusions: Different analytical methods of changes in HRQoL result in distinct conclusions of treatment effects, all of which may be relevant for informing clinical decision making.
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http://dx.doi.org/10.1093/nop/npaa033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716184PMC
December 2020

Memory in low-grade glioma patients treated with radiotherapy or temozolomide: a correlative analysis of EORTC study 22033-26033.

Neuro Oncol 2021 05;23(5):803-811

Department of Radiation Oncology (MAASTRO), GROW‒School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: EORTC study 22033-26033 showed no difference in progression-free survival between high-risk low-grade glioma receiving either radiotherapy (RT) or temozolomide (TMZ) chemotherapy alone as primary treatment. Considering the potential long-term deleterious impact of RT on memory functioning, this study aims to determine whether TMZ is associated with less impaired memory functioning.

Methods: Using the Visual Verbal Learning Test (VVLT), memory functioning was evaluated at baseline and subsequently every 6 months. Minimal compliance for statistical analyses was set at 60%. Conventional indices of memory performance (VVLT Immediate Recall, Total Recall, Learning Capacity, and Delayed Recall) were used as outcome measures. Using a mixed linear model, memory functioning was compared between treatment arms and over time.

Results: Neuropsychological assessment was performed in 98 patients (53 RT, 46 TMZ). At 12 months, compliance had dropped to 66%, restricting analyses to baseline, 6 months, and 12 months. At baseline, patients in either treatment arm did not differ in memory functioning, sex, age, or educational level. Over time, patients in both arms showed improvement in Immediate Recall (P = 0.017) and total number of words recalled (Total Recall; P < 0.001, albeit with delayed improvement in RT patients (group by time; P = 0.011). Memory functioning was not associated with RT gross, clinical, or planned target volumes.

Conclusion: In patients with high-risk low-grade glioma there is no indication that in the first year after treatment, RT has a deleterious effect on memory function compared with TMZ chemotherapy.
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http://dx.doi.org/10.1093/neuonc/noaa252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099470PMC
May 2021

Radiation for Relapse.

Int J Radiat Oncol Biol Phys 2020 11;108(3):521

Institute of Radiation-Oncology, Cantonal Hospital Graubünden, Chur, Switzerland.

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http://dx.doi.org/10.1016/j.ijrobp.2020.01.036DOI Listing
November 2020

A cancer drug atlas enables synergistic targeting of independent drug vulnerabilities.

Nat Commun 2020 06 10;11(1):2935. Epub 2020 Jun 10.

Experimental Therapeutics and Molecular Imaging Lab, Neuroscience Center, Neuro-Oncology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Personalized cancer treatments using combinations of drugs with a synergistic effect is attractive but proves to be highly challenging. Here we present an approach to uncover the efficacy of drug combinations based on the analysis of mono-drug effects. For this we used dose-response data from pharmacogenomic encyclopedias and represent these as a drug atlas. The drug atlas represents the relations between drug effects and allows to identify independent processes for which the tumor might be particularly vulnerable when attacked by two drugs. Our approach enables the prediction of combination-therapy which can be linked to tumor-driving mutations. By using this strategy, we can uncover potential effective drug combinations on a pan-cancer scale. Predicted synergies are provided and have been validated in glioblastoma, breast cancer, melanoma and leukemia mouse-models, resulting in therapeutic synergy in 75% of the tested models. This indicates that we can accurately predict effective drug combinations with translational value.
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http://dx.doi.org/10.1038/s41467-020-16735-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287046PMC
June 2020

Whole-lung Low Dose Irradiation for SARS-Cov2 Induced Pneumonia in the Geriatric Population: An Old Effective Treatment for a New Disease? Recommendation of the International Geriatric Radiotherapy Group.

Aging Dis 2020 May 9;11(3):489-493. Epub 2020 May 9.

15Department of Radiation Oncology, Baclesse Cancer Center, Caen, France.

A cytokine storm induced by SARS-Cov2 may produce pneumonitis which may be fatal for older patients with underlying lung disease. Hyper-elevation of Interleukin1 (IL-1), Tumor necrosis factor-1alfa (TNF-1 alfa), and Interleukin 6 (IL-6) produced by inflammatory macrophage M1 may damage the lung alveoli leading to severe pneumonitis, decreased oxygenation, and potential death despite artificial ventilation. Older patients may not be suitable candidates for pharmaceutical intervention targeting IL-1/6 blockade or artificial ventilation. Low dose total lung (LDTL) irradiation at a single dose of 50 cGy may stop this cytokine cascade, thus preventing, and/or reversing normal organs damage. This therapy has been proven in the past to be effective against pneumonitis of diverse etiology and could be used to prevent death of older infected patients. Thus, LDRT radiotherapy may be a cost-effective treatment for this frail patient population whom radiation -induced malignancy is not a concern because of their advanced age. This hypothesis should be tested in future prospective trials.
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http://dx.doi.org/10.14336/AD.2020.0506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220282PMC
May 2020

Radiotherapy in the treatment of extracranial hemangiopericytoma/solitary fibrous tumor: Study from the Rare Cancer Network.

Radiother Oncol 2020 03 2;144:114-120. Epub 2019 Dec 2.

Dept. Of Radiation Oncology, Centre A. Lacassagne, Nice, France; Dept. of Radiation Oncology, Centre F. Baclesse, Caen, France.

Background And Purpose: The role of radiotherapy (RT) in the treatment of hemangiopericytoma/solitary fibrous tumor (HPC/SFT) is still under debate. We aimed at investigating whether radiotherapy can improve the results in patients operated for extracranial HPC/SFT.

Materials And Methods: Data from patients with HPC/SFT, treated from 1982 to 2012, were retrospectively reviewed within the Rare Cancer Network framework. Actuarial local control (LC), disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) were calculated with Kaplan-Meyer method. Patient and tumor parameters were analyzed by univariate and multivariate analysis.

Results: Of 114 HPC/SFT, 58 (50.9%) occurred in the extremities/superficial trunk and 56 (49.1%) in intra-thoracic/retroperitoneum. Seventy-eight patients (68.4%) underwent surgery only (Sx), and 36 (31.6%) Sx and RT (Sx + RT). Median RT dose was 60 Gy (range 45-68.4 Gy) in 1.6-2.2 Gy fractions. In the extremities/superficial trunk group of patients, actuarial 5-year LC rates were 50.4% after Sx and 91.6% after Sx + RT (p < 0.0001) for LC, and 50.4% after Sx and 83.1% after Sx + RT (p = 0.008) for DFS. In the intra-thoracic/retroperitoneum group of patients, actuarial 5-year rates were 89.3% after Sx and 77.8% after Sx + RT (p = 0.99) for LC, and 73.8% after Sx and 77.8% after Sx + RT (p = 0.93) for DFS. At multivariate analysis, the addition of RT resulted in better LC and DFS in the whole series. The advantage was confirmed for LC in the group of patients affected by extremity/superficial trunk tumors.

Conclusion: Addition of RT to Sx could improve the prognosis, in terms of LC and DFS, essentially in patients with extremities/superficial trunk tumor locations.
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http://dx.doi.org/10.1016/j.radonc.2019.11.011DOI Listing
March 2020

Symptom clusters in newly diagnosed glioma patients: which symptom clusters are independently associated with functioning and global health status?

Neuro Oncol 2019 11;21(11):1447-1457

Department of Neurology, Leiden University Medical Center, Leiden, Netherlands.

Background: Symptom management in glioma patients remains challenging, as patients suffer from various concurrently occurring symptoms. This study aimed to identify symptom clusters and examine the association between these symptom clusters and patients' functioning.

Methods: Data of the CODAGLIO project was used, including individual patient data from previously published international randomized controlled trials (RCTs) in glioma patients. Symptom prevalence and level of functioning were assessed with European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C30 and QLQ-BN20 self-report questionnaires. Associations between symptoms were examined with Spearman correlation coefficients and partial correlation networks. Hierarchical cluster analyses were performed to identify symptom clusters. Multivariable regression analyses were performed to determine independent associations between the symptom clusters and functioning, adjusted for possible confounders.

Results: Included in the analysis were 4307 newly diagnosed glioma patients from 11 RCTs who completed the EORTC questionnaires before randomization. Many patients (44%) suffered from 5-10 symptoms simultaneously. Four symptom clusters were identified: a motor cluster, a fatigue cluster, a pain cluster, and a gastrointestinal/seizures/bladder control cluster. Having symptoms in the motor cluster was associated with decreased (≥10 points difference) physical, role, and social functioning (betas ranged from -11.3 to -15.9, all P < 0.001), independent of other factors. Similarly, having symptoms in the fatigue cluster was found to negatively influence role functioning (beta of -12.3, P < 0.001), independent of other factors.

Conclusions: Two symptom clusters, the fatigue and motor cluster, were frequently affected in glioma patients and were found to independently have a negative association with certain aspects of patients' functioning as measured with a self-report questionnaire.
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http://dx.doi.org/10.1093/neuonc/noz118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6827824PMC
November 2019

Evaluation of the Hippocampal Normal Tissue Complication Model in a Prospective Cohort of Low Grade Glioma Patients-An Analysis Within the EORTC 22033 Clinical Trial.

Front Oncol 2019 1;9:991. Epub 2019 Oct 1.

Department of Medical Psychology, University Medical Center Amsterdam, Amsterdam, Netherlands.

To evaluate the performance of the hippocampal normal tissue complication model that relates dose to the bilateral hippocampus to memory impairment at 18 months post-treatment in a population of low-grade glioma (LGG) patients. LGG patients treated within the radiotherapy-only arm of the EORTC 22033-26033 trial were analyzed. Hippocampal dose parameters were calculated from the original radiotherapy plans. Difference in Rey Verbal Auditory Learning test delayed recall (AVLT-DR) performance pre-and 18 (±4) months post-treatment was compared to reference data from the Maastricht Aging study. The NTCP model published by Gondi et al. was applied to the dosimetric data and model predictions were compared to actual neurocognitive outcome. A total of 29 patients met inclusion criteria. Mean dose in EQD2 Gy to the bilateral hippocampus was 39.8 Gy (95% CI 34.3-44.4 Gy), the median dose to 40% of the bilateral hippocampus was 47.2 EQD2 Gy. The model predicted a risk of memory impairment exceeding 99% in 22 patients. However, only seven patients were found to have a significant decline in AVLT-dr score. In this dataset of only LGG patients treated with radiotherapy the hippocampus NTCP model did not perform as expected to predict cognitive decline based on dose to 40% of the bilateral hippocampus. Caution should be taken when extrapolating this model outside of the range of dose-volume parameters in which it was developed.
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http://dx.doi.org/10.3389/fonc.2019.00991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797857PMC
October 2019

The added value of health-related quality of life as a prognostic indicator of overall survival and progression-free survival in glioma patients: a meta-analysis based on individual patient data from randomised controlled trials.

Eur J Cancer 2019 07 13;116:190-198. Epub 2019 Jun 13.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands; Department of Neurology, Haaglanden Medical Center, Den Haag, the Netherlands.

Objective: Prognostic value of health-related quality of life (HRQoL) data may be important to inform patients in clinical practice and to guide clinical decision-making. Our study investigated the added prognostic value of HRQoL for overall survival (OS) and progression-free survival (PFS) in a large heterogeneous sample of glioma patients, besides known prognostic factors.

Methods: We included individual baseline data from previously published randomised controlled trials (RCTs) in glioma patients in which HRQoL was assessed through the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BN20 questionnaires. Multivariable Cox regression models (stratified for newly diagnosed versus recurrent disease) were constructed, first with clinical variables (age, sex, tumour type, performance status, allocated treatment and extent of resection) only and subsequently with HRQoL variables added, separately for OS and PFS. The added prognostic value of HRQoL was calculated using C-indices.

Results: Baseline HRQoL and clinical data from 15 RCTs were included, comprising 5217 patients. In the model including both clinical and HRQoL variables, better cognitive and role functioning and less motor dysfunction were independently associated with longer OS, whereas better role and cognitive functioning, less nausea and vomiting and more appetite loss were independently associated with prolonged PFS. However, C-indices indicated only a small prognostic improvement of the models for OS and PFS when adding HRQoL to the clinical prognostic variables (+1.1% for OS and +.7% for PFS).

Conclusion: Our findings demonstrate that several baseline HRQoL variables are independently prognostic for OS and PFS, yet the added value of HRQoL to the known clinical prognostic variables was small.
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http://dx.doi.org/10.1016/j.ejca.2019.05.012DOI Listing
July 2019

Challenges Facing Radiation Oncologists in The Management of Older Cancer Patients: Consensus of The International Geriatric Radiotherapy Group.

Cancers (Basel) 2019 Mar 16;11(3). Epub 2019 Mar 16.

Department of Radiation Oncology, Sant Joan de Reus University, University Rovira i Virgili, Tarragona 43204, Spain.

The management of older cancer patients remains difficult because of data paucity. Radiation oncologists need to identify potential issues which could affect treatment of those patients. A workshop was organized in Barcelona among international radiation oncologists with special interest in the management of older cancer patients on April 22, 2018. The following consensus was reached: 1. Older cancer patients often faced unconscious discriminating bias from cancer specialists and institutions because of their chronological age. 2. Advances in radiotherapy techniques have allowed patients with multiple co-morbidities precluding surgery or systemic therapy to achieve potential cure in early disease stages. 3. The lack of biomarkers for frailty remains an impediment to future research. 4. Access to healthcare insurance and daily transportation remains an issue in many countries; 5. Hypofractionation, brachytherapy, or stereotactic techniques may be ideally suited for older cancer patients to minimize transportation issues and to improve tolerance to radiotherapy. 6. Patients with locally advanced disease who are mentally and physically fit should receive combined therapy for potential cure. 7. The role of systemic therapy alone or combined with radiotherapy for frail patients needs to be defined in future clinical trials because of targeted agents or immunotherapy may be less toxic compared to conventional chemotherapy.
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http://dx.doi.org/10.3390/cancers11030371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6468336PMC
March 2019

Impact of Radiation Target Volume on Health-Related Quality of Life in Patients With Low-Grade Glioma in the 2-Year Period Post Treatment: A Secondary Analysis of the EORTC 22033-26033.

Int J Radiat Oncol Biol Phys 2019 05 2;104(1):90-100. Epub 2019 Feb 2.

Klinik für Strahlentherapie und Radioonkologie, Universitätsklinikum Leipzig, Leipzig, Germany. Electronic address:

Purpose: It is currently unknown whether increasing radiation therapy (RT) volume has a negative impact on the health-related quality of life (HRQoL) of patients with low-grade glioma in the short term. The aim was to examine whether the size of the target volume is independently associated with HRQoL.

Methods And Materials: We included patients who were treated with radiation therapy in the European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 study and who completed baseline HRQoL assessment. HRQoL was measured at baseline and every 3 months thereafter until progression, using the European Organisation for Research and Treatment of Cancer quality of life and brain cancer module questionnaires (QLQ-C30 and QLQ-BN20). We investigated whether there were associations between radiation volumes and (changes in) 4 preselected HRQoL scales (global health status, cognitive and social functioning, and fatigue). Also, we determined if radiation volumes were independently associated with a change in HRQoL over time.

Results: We included 195 of 240 patients (81.3%) randomized to radiation therapy in this analysis. The brain volume receiving radiation therapy was not associated with (changes in) HRQoL during the first 24 months after radiation therapy. Over time, radiation volumes were also not independently associated with HRQoL. Notably, the occurrence of tumor progression was found to be associated with worse functioning and more fatigue.

Conclusions: The brain target volume receiving focal radiation therapy in fractions of 1.8 Gy to a total of 50.4 Gy did not appear to be independently associated with HRQoL in high-risk patients with low-grade glioma in the short term, as opposed to tumor progression. However, the impact of radiation volumes on long-term HRQoL, as well as neurocognitive functioning, remains to be investigated.
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http://dx.doi.org/10.1016/j.ijrobp.2019.01.003DOI Listing
May 2019

Adjuvant postoperative high-dose radiotherapy for atypical and malignant meningioma: A phase-II parallel non-randomized and observation study (EORTC 22042-26042).

Radiother Oncol 2018 08 28;128(2):260-265. Epub 2018 Jun 28.

EORTC Headquarters, Brussels, Belgium.

Purpose: The therapeutic strategy for non-benign meningiomas is controversial. The objective of this study was to prospectively investigate the impact of high dose radiation therapy (RT) on the progression-free survival (PFS) rate at 3 years in WHO grade II and III meningioma patients.

Materials And Methods: In this multi-cohorts non-randomized phase II and observational study, non-benign meningioma patients were treated according to their WHO grade and Simpson's grade. Patients with atypical meningioma (WHO grade II) and Simpson's grade 1-3 [Arm 1] entered the non-randomized phase II study designed to show a 3-year PFS > 70% (primary endpoint). All other patients entered the 3 observational cohorts: WHO grade II Simpson grade 4-5 [Arm 2] and Grade III Simpson grade 1-3 or 4-5 [Arm 3&4] in which few patients were expected.

Results: Between 02/2008 and 06/2013, 78 patients were enrolled into the study. This report focuses on the 56 (median age, 54 years) eligible patients with WHO grade II Simpson's grade 1-3 meningioma who received RT (60 Gy). At a median follow up of 5.1 years, the estimated 3-year PFS is 88.7%, hence significantly greater than 70%. Eight (14.3%) treatment failures were observed. The 3-year overall survival was 98.2%. The rate of late signs and symptoms grade 3 or more was 14.3%.

Conclusions: These data show that 3-year PFS for WHO grade II meningioma patients undergoing a complete resection (Simpson I-III) is superior to 70% when treated with high-dose (60 Gy) RT.
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http://dx.doi.org/10.1016/j.radonc.2018.06.018DOI Listing
August 2018

Novel, improved grading system(s) for IDH-mutant astrocytic gliomas.

Acta Neuropathol 2018 07 23;136(1):153-166. Epub 2018 Apr 23.

Department of Neurosurgery, University Medical Center Mannheim, University of Heidelberg, Mannheim, Germany.

According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII), and WHO grade IV glioblastoma, IDH-mutant (GBM). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII and AAIII have lost their significance. In contrast, GBM still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
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http://dx.doi.org/10.1007/s00401-018-1849-4DOI Listing
July 2018

Radiotherapy quality assurance for the RTOG 0834/EORTC 26053-22054/NCIC CTG CEC.1/CATNON intergroup trial "concurrent and adjuvant temozolomide chemotherapy in newly diagnosed non-1p/19q deleted anaplastic glioma": Individual case review analysis.

Radiother Oncol 2018 May 29;127(2):292-298. Epub 2018 Mar 29.

Center for Proton Therapy, Paul Scherrer Institute, ETH Domain, Villigen, Switzerland; University Hospital of Zürich, Switzerland.

Background: The EORTC phase III 26053-22054/ RTOG 0834/NCIC CTG CEC.1/CATNON intergroup trial was designed to evaluate the impact on concurrent and adjuvant temozolomide chemotherapy in newly diagnosed non-1p/19q deleted anaplastic gliomas. The primary endpoint was overall survival. We report the results of retrospective individual case reviews (ICRs) for the first patient randomized per institution to detect the compliance with the study protocol.

Material And Methods: Sixty-nine institutions were required to submit the radiotherapy plan of their first randomized patient. Full digital datasets uploaded to the EORTC server were assessed by three independent and blinded reviewers through the EORTC radiotherapy quality assurance platform.

Results: Sixty-two (90%) of sixty-nine ICRs were received and assessable. Of the 62 cases, 22 were evaluated as per protocol (35.5%), 11 as acceptable variation (17.7%) and 29 were classified as unacceptable variations (46.8%). Most common unacceptable variations were related to the PTV dose (n = 19, 31%) and delineation (n = 17, 27%) processes.

Conclusions: The ICR analysis showed a significant number of unacceptable variations with potential impact on tumor control and/or toxicity profile. Prospective ICRs are encouraged for future studies to prevent and correct protocol violations before start of treatment.
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http://dx.doi.org/10.1016/j.radonc.2018.03.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6258055PMC
May 2018

Treatment outcome and prognostic factors for adult patients with medulloblastoma: The Rare Cancer Network (RCN) experience.

Radiother Oncol 2018 Apr 17;127(1):96-102. Epub 2018 Jan 17.

Department of Radiation Oncology, Mayo Clinic Hospital, Phoenix, AZ, United States.

Background And Purpose: The optimal treatment for adults with newly diagnosed medulloblastoma (MB) has not been defined. We report a large series of cases from the Rare Cancer Network.

Material And Methods: Thirteen institutions enrolled 206 MB patients who underwent postoperative radiotherapy (RT) between 1976 and 2014. Log-rank univariate and Cox-modeled multivariate analyses were used to analyze data collected.

Results: Median patient age was 29 years; follow-up was 31 months. All patients had the tumor resected; surgery was complete in 140 (68%) patients. Postoperative RT was given in 202 (98%) patients, and 94% received craniospinal irradiation (CSI) and, usually, a posterior fossa boost. Ninety-eight (48%) patients had chemotherapy, mostly cisplatin and vincristine-based. The 10-year local control, overall survival, and disease-free survival rates were 46%, 51%, and 38%, respectively. In multivariate analyses, Karnofsky Performance Status (KPS) ≥80 and CSI were significant for disease-free and overall survival (P ≤ .04 for all); receiving chemotherapy and KPS ≥80 correlated with better local-control rates.

Conclusions: Patients with high KPS who received CSI had better rates of disease-free and overall survival. Chemotherapy was associated with better local control. These results may serve as a benchmark for future studies designed to improve outcomes for adults with medulloblastoma.
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http://dx.doi.org/10.1016/j.radonc.2017.12.028DOI Listing
April 2018

The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033.

Acta Neuropathol 2018 04 24;135(4):601-615. Epub 2018 Jan 24.

Laboratory of Brain Tumor Biology and Genetics, Neuroscience Research Center, Lausanne University Hospital, Chemin des Boveresses 155, CLE-C306, 1066 Epalinges, Lausanne, Switzerland.

The optimal treatment for patients with low-grade glioma (LGG) WHO grade II remains controversial. Overall survival ranges from 2 to over 15 years depending on molecular and clinical factors. Hence, risk-adjusted treatments are required for optimizing outcome and quality of life. We aim at identifying mechanisms and associated molecular markers predictive for benefit from radiotherapy (RT) or temozolomide (TMZ) in LGG patients treated in the randomized phase III trial EORTC 22033. As candidate biomarkers for these genotoxic treatments, we considered the DNA methylome of 410 DNA damage response (DDR) genes. We first identified 62 functionally relevant CpG sites located in the promoters of 24 DDR genes, using the LGG data from The Cancer Genome Atlas. Then we tested their association with outcome [progression-free survival (PFS)] depending on treatment in 120 LGG patients of EORTC 22033, whose tumors were mutant for isocitrate dehydrogenase 1 or 2 (IDHmt), the molecular hallmark of LGG. The results suggested that seven CpGs of four DDR genes may be predictive for longer PFS in one of the treatment arms that comprised MGMT, MLH3, RAD21, and SMC4. Most interestingly, the two CpGs identified for MGMT are the same, previously selected for the MGMT-STP27 score that is used to determine the methylation status of the MGMT gene. This score was higher in the LGG with 1p/19q codeletion, in this and other independent LGG datasets. It was predictive for PFS in the TMZ, but not in the RT arm of EORTC 22033. The results support the hypothesis that a high score predicts benefit from TMZ treatment for patients with IDHmt LGG, regardless of the 1p/19q status. This MGMT methylation score may identify patients who benefit from first-line treatment with TMZ, to defer RT for long-term preservation of cognitive function and quality of life.
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http://dx.doi.org/10.1007/s00401-018-1810-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5978935PMC
April 2018

Clinical trial design for local therapies for brain metastases: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group.

Lancet Oncol 2018 01;19(1):e33-e42

Center for Neuro-Oncology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Boston, MA, USA.

The goals of therapeutic and biomarker development form the foundation of clinical trial design, and change considerably from early-phase to late-phase trials. From these goals, decisions on specific clinical trial design elements, such as endpoint selection and statistical approaches, are formed. Whereas early-phase trials might focus on finding a therapeutic signal to make decisions on further development, late-phase trials focus on the confirmation of therapeutic impact by considering clinically meaningful endpoints. In this guideline from the Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group, we highlight issues related to, and provide recommendations for, the design of clinical trials on local therapies for CNS metastases from solid tumours. We discuss endpoint selection criteria, the analysis appropriate for early-phase and late-phase trials, the association between tumour-specific and clinically meaningful endpoints, and possible issues related to the estimation of local control in the context of competing risks. In light of these discussions, we make specific recommendations on the clinical trial design of local therapies for brain metastases.
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http://dx.doi.org/10.1016/S1470-2045(17)30692-7DOI Listing
January 2018

Identification of MEK162 as a Radiosensitizer for the Treatment of Glioblastoma.

Mol Cancer Ther 2018 02 27;17(2):347-354. Epub 2017 Sep 27.

Department of Radiation Oncology, VU University Medical Center, Amsterdam, the Netherlands.

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied preclinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small-molecule drugs including MK2206, RAD001, BEZ235, MLN0128, and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction, and time to regrow), cell-cycle distribution and expression of key target proteins were evaluated. , the effect of irradiation (3 × 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK-targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 downregulated and dephosphorylated the cell-cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation, this led to a prolonged DNA damage signal. data on tumor-bearing animals demonstrated a significantly reduced growth rate, increased growth delay, and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as a radiosensitizer in GBM spheroids and in orthotopic GBM xenografts The data are supportive for implementation of this targeted agent in an early-phase clinical study in GBM patients.
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http://dx.doi.org/10.1158/1535-7163.MCT-17-0480DOI Listing
February 2018

Evidence-based management of adult patients with diffuse glioma - Authors' reply.

Lancet Oncol 2017 08 26;18(8):e430-e431. Epub 2017 Jul 26.

Neurology Clinic and National Centre for Tumour Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Consortium of Translational Cancer Research, Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany.

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http://dx.doi.org/10.1016/S1470-2045(17)30515-6DOI Listing
August 2017

European Association for Neuro-Oncology (EANO) guideline on the diagnosis and treatment of adult astrocytic and oligodendroglial gliomas.

Lancet Oncol 2017 06 5;18(6):e315-e329. Epub 2017 May 5.

Neurology Clinic and National Centre for Tumour Diseases, University Hospital Heidelberg, Heidelberg, Germany; German Consortium of Translational Cancer Research (DKTK), Clinical Cooperation Unit Neurooncology, German Cancer Research Center, Heidelberg, Germany.

The European Association for Neuro-Oncology guideline provides recommendations for the clinical care of adult patients with astrocytic and oligodendroglial gliomas, including glioblastomas. The guideline is based on the 2016 WHO classification of tumours of the central nervous system and on scientific developments since the 2014 guideline. The recommendations focus on pathological and radiological diagnostics, and the main treatment modalities of surgery, radiotherapy, and pharmacotherapy. In this guideline we have also integrated the results from contemporary clinical trials that have changed clinical practice. The guideline aims to provide guidance for diagnostic and management decisions, while limiting unnecessary treatments and costs. The recommendations are a resource for professionals involved in the management of patients with glioma, for patients and caregivers, and for health-care providers in Europe. The implementation of this guideline requires multidisciplinary structures of care, and defined processes of diagnosis and treatment.
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http://dx.doi.org/10.1016/S1470-2045(17)30194-8DOI Listing
June 2017

Is more better? The impact of extended adjuvant temozolomide in newly diagnosed glioblastoma: a secondary analysis of EORTC and NRG Oncology/RTOG.

Neuro Oncol 2017 Aug;19(8):1119-1126

Tel-Aviv Sourasky Medical Center, Tel-Aviv University; European Organization for Research and Treatment of Cancer, Brussels (EORTC); National Institutes of Health (M.R.M.); University of Alabama at Birmingham; Princess Margaret Cancer Centre, University of Toronto; Lausanne University Hospital; NRG Oncology Statistics and Data Management Center; Odette Cancer Centre and Sunnybrook Health Sciences Centre, University of Toronto; Samsung Medical Center, Sungkyunkwan University School of Medicine; Edinburgh Cancer Centre; Mayo Clinic; Robert-Janker Clinic at the University of Bonn Medical Centre, and MAASTRO clinic, GROW School for Oncology, Maastricht University Medical Centre; Miami Cancer Institute; Erasmus University Hospital; Dana-Farber Cancer Institute and Harvard Medical School; University of Zurich.

Background: Radiation with concurrent and adjuvant (6 cycles) temozolomide (TMZ) is the established standard of postsurgical care for newly diagnosed glioblastoma (GBM). This regimen has been adopted with variations, including extending TMZ beyond 6 cycles. The optimal duration of maintenance therapy remains controversial.

Methods: We performed pooled analysis of individual patient data from 4 randomized trials for newly diagnosed GBM. All patients who were progression free 28 days after cycle 6 were included. The decision to continue TMZ was per local practice and standards, and at the discretion of the treating physician. Patients were grouped into those treated with 6 cycles and those who continued beyond 6 cycles. Progression-free and overall survival were compared, adjusted by age, performance status, resection extent, and MGMT methylation.

Results: A total of 2214 GBM patients were included in the 4 trials. Of these, 624 qualified for analysis 291 continued maintenance TMZ until progression or up to 12 cycles, while 333 discontinued TMZ after 6 cycles. Adjusted for prognostic factors, treatment with more than 6 cycles of TMZ was associated with a somewhat improved progression-free survival (hazard ratio [HR] 0.80 [0.65-0.98], P = .03), in particular for patients with methylated MGMT (n = 342, HR 0.65 [0.50-0.85], P < .01). However, overall survival was not affected by the number of TMZ cycles (HR = 0.92 [0.71-1.19], P = .52), including the MGMT methylated subgroup (HR = 0.89 [0.63-1.26], P = .51).

Conclusions: Continuing TMZ beyond 6 cycles was not shown to increase overall survival for newly diagnosed GBM.
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http://dx.doi.org/10.1093/neuonc/nox025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570239PMC
August 2017

The allosteric AKT inhibitor MK2206 shows a synergistic interaction with chemotherapy and radiotherapy in glioblastoma spheroid cultures.

BMC Cancer 2017 03 21;17(1):204. Epub 2017 Mar 21.

Department of Radiation Oncology, VU University Medical Center/Cancer Center Amsterdam, P.O. Box 7057, Amsterdam, 1007, MB, The Netherlands.

Background: Glioblastoma multiforme (GBM) is the most common, invasive and deadly primary type of malignant brain tumor. The Phosphatidylinositol-3-Kinase/AKT (PI3K/AKT) pathway is highly active in GBM and has been associated with increased survival and resistance to therapy. The aim of this study is to investigate the effects of AKT inhibition in combination with the current standard of care which consists of irradiation and temozolomide (TMZ) on human malignant glioma cells growing adherent and as multicellular spheroids in vitro.

Methods: The effects of the allosteric inhibitor MK2206 combined with irradiation and TMZ were assessed on glioma cells growing adherent and as multicellular 3D spheroids. The interaction was studied on proliferation, clonogenic cell survival, cell invasion, -migration and on expression of key proteins in the PI3K-AKT pathway by western blot.

Results: A differential effect was found at low- (1 μM) and high dose (10 μM) MK2206. At 1 μM, the inhibitor reduced phosphorylation of Thr308 and Ser473 residues of AKT in both adherent cells and spheroids. Low dose MK2206 delayed spheroid growth and sensitized spheroids to both irradiation and TMZ in a synergistic way (Combination index <0.35). In contrast, neither low nor high dose MK2206 did enhance therapy sensitivity in adherent growing cells. Effective inhibition of invasion and migration was observed only at higher doses of MK2206 (>5 μM).

Conclusions: The data show that a 3D spheroid model show different sensitivity to irradiation when combined with AKT inhibition. Thereby we show that MK2206 has potential synergistic efficacy to the current standard of care for glioma patients.
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http://dx.doi.org/10.1186/s12885-017-3193-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359921PMC
March 2017

Short-Course Radiation plus Temozolomide in Elderly Patients with Glioblastoma.

N Engl J Med 2017 03;376(11):1027-1037

From Odette Cancer Centre, Sunnybrook Health Sciences Centre (J.R.P., A.S.) and Princess Margaret Cancer Centre (N.L., W.P.M.), Toronto, the Canadian Cancer Trials Group, Queens University, Kingston, ON (C.J.O., C.W., K.D.), University of Calgary, Calgary, AB (J.G.C.), University of Alberta, Edmonton (W.R.), Quality of Life Consulting, West Vancouver, BC (D.O.), Queen's University, Kingston General Hospital, Kingston, ON (J.P.R.), and Juravinski Cancer Centre, Hamilton, ON (H.H.) - all in Canada; Azienda Unità Sanitaria Locale- Istituto di Ricovero e Cura a Carattere Scientifico Istituto delle Scienze Neurologiche, Bologna (A.A.B., E.F.), and Fondazione Istituto Neurologico Carlo Besta, Milan (L. Fariselli) - both in Italy; University Hospital Gasthuisberg, Leuven, Belgium (J.M.); Peter MacCallum Cancer Centre, Melbourne, VIC (C.P.), University of Newcastle, Newcastle, NSW (M.F.), University of Queensland, Brisbane (M.F.), and Royal North Shore Hospital, Sydney (M.B.) - all in Australia; Saitama Medical University International Medical Center, Saitama, Japan (R.N.); Hôpital de la Pitié-Salpêtrière (F.L.-D., L. Feuvret), Paris, and Aix-Marseille University, Assistance Publique-Hôpitaux de Marseille, Centre Hospitalier Universitaire Timone, Marseilles (O.C.) - both in France; the European Organization for Research and Treatment of Cancer, Brussels (V.G.); the Neurology Clinic, University of Heidelberg, Heidelberg, Germany (A.W., W.W.); Tauranga Hospital, Tauranga, New Zealand (M.T.); and Maastricht University Medical Center and School for Oncology and Developmental Biology, Maastricht, the Netherlands (B.G.B.).

Background: Glioblastoma is associated with a poor prognosis in the elderly. Survival has been shown to increase among patients 70 years of age or younger when temozolomide chemotherapy is added to standard radiotherapy (60 Gy over a period of 6 weeks). In elderly patients, more convenient shorter courses of radiotherapy are commonly used, but the benefit of adding temozolomide to a shorter course of radiotherapy is unknown.

Methods: We conducted a trial involving patients 65 years of age or older with newly diagnosed glioblastoma. Patients were randomly assigned to receive either radiotherapy alone (40 Gy in 15 fractions) or radiotherapy with concomitant and adjuvant temozolomide.

Results: A total of 562 patients underwent randomization, 281 to each group. The median age was 73 years (range, 65 to 90). The median overall survival was longer with radiotherapy plus temozolomide than with radiotherapy alone (9.3 months vs. 7.6 months; hazard ratio for death, 0.67; 95% confidence interval [CI], 0.56 to 0.80; P<0.001), as was the median progression-free survival (5.3 months vs. 3.9 months; hazard ratio for disease progression or death, 0.50; 95% CI, 0.41 to 0.60; P<0.001). Among 165 patients with methylated O-methylguanine-DNA methyltransferase (MGMT) status, the median overall survival was 13.5 months with radiotherapy plus temozolomide and 7.7 months with radiotherapy alone (hazard ratio for death, 0.53; 95% CI, 0.38 to 0.73; P<0.001). Among 189 patients with unmethylated MGMT status, the median overall survival was 10.0 months with radiotherapy plus temozolomide and 7.9 months with radiotherapy alone (hazard ratio for death, 0.75; 95% CI, 0.56 to 1.01; P=0.055; P=0.08 for interaction). Quality of life was similar in the two trial groups.

Conclusions: In elderly patients with glioblastoma, the addition of temozolomide to short-course radiotherapy resulted in longer survival than short-course radiotherapy alone. (Funded by the Canadian Cancer Society Research Institute and others; ClinicalTrials.gov number, NCT00482677 .).
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http://dx.doi.org/10.1056/NEJMoa1611977DOI Listing
March 2017

Current management of low-grade gliomas.

Curr Opin Neurol 2016 12;29(6):782-788

aDepartment of Clinical Neurosciences bDepartment of Oncology, Centre Hospitalier Universitaire Vaudois & Lausanne University, Lausanne, Switzerland cDepartment of Radiation-Oncology (MAASTRO), Maastricht University Medical Center (MUMC) and GROW (School for Oncology), Maastricht, Netherlands dDepartment of Radiation-Oncology, MediClin Robert-Janker-Clinic & Clinical Cooperation Unit Neurooncology, University Bonn Medical Centre, Bonn, Germany *Andreas F. Hottinger, Monika E. Hegi and Brigitta G. Baumert contributed equally to the article.

Purpose Of Review: The management of patients suffering from low-grade gliomas (LGGs) remains a challenge in absence of a definite curative therapy. The median survival is highly variable, from 2 years (high-risk disease) to over 15 years (low risk). The aim of this review is to provide a practical step-by-step evaluation of the available treatment options for patients with LGGs.

Recent Findings: Next to clinical prognostic markers, both the isocitrate dehydrogenase (IDH) mutation status and the status of 1p/19q codeletion are key prognostic factors for the optimal management of patients with LGG. Two recent randomized phase III clinical trials were performed in LGGs. They first compared the efficacy of radiation versus temozolomide (TMZ) chemotherapy in high-risk LGGs. The second trial compared radiation versus radiation combined with procarbazine, lomustine and vincristine chemotherapy.

Summary: Regarding molecular prognostic factors, IDH wild-type LGGs have the worst prognosis, independent of therapy, whereas patients with mutated IDH, codeleted 1p/19q LGGs fared best regarding progression-free survival (PFS). In high-risk LGGs, PFS is similar regardless of whether patients have been treated with radiation or TMZ. In the second trial, patients who were treated with combination radiation and chemotherapy showed significant longer overall survival.
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http://dx.doi.org/10.1097/WCO.0000000000000390DOI Listing
December 2016