Kerkhof M.,Neuro oncology Unit |
Dielemans J.C.M.,Neuro oncology Unit |
Van Breemen M.S.,Neuro oncology Unit |
Zwinkels H.,Neuro oncology Unit |
And 4 more authors.
Neuro-Oncology | Year: 2013
Background: To examine the efficacy of valproic acid (VPA) given either with or without levetiracetam (LEV) on seizure control and on survival in patients with glioblastoma multiforme (GBM) treated with chemoradiation. Methods: A retrospective analysis was performed on 291 patients with GBM. The efficacies of VPA and LEV alone and as polytherapy were analyzed in 181 (62%) patients with seizures with a minimum follow-up of 6 months. Cox-regression survival analysis was performed on 165 patients receiving chemoradiation with temozolomide of whom 108 receiving this in combination with VPA for at least 3 months. Results: Monotherapy with either VPA or LEV was instituted in 137/143 (95.8%) and in 59/86 (68.6%) on VPA/LEV polytherapy as the next regimen. Initial freedom from seizure was achieved in 41/100 (41%) on VPA, in 16/37 (43.3%) on LEV, and in 89/116 (76.7%) on subsequent VPA/LEV polytherapy. At the end of follow-up, seizure freedom was achieved in 77.8% (28/36) on VPA alone, in 25/36 (69.5%) on LEV alone, and in 38/63 (60.3%) on VPA/LEV polytherapy with ongoing seizures on monotherapy. Patients using VPA in combination with temozolomide showed a longer median survival of 69 weeks (95% confidence interval [CI]: 61.7-67.3) compared with 61 weeks (95% CI: 52.5-69.5) in the group without VPA (hazard ratio, 0.63; 95% CI: 0.43-0.92; P =. 016), adjusting for age, extent of resection, and O6-DNA methylguanine-methyltransferase promoter methylation status. Conclusions: Polytherapy with VPA and LEV more strongly contributes to seizure control than does either as monotherapy. Use of VPA together with chemoradiation with temozolomide results in a 2-months' longer survival of patients with GBM. © 2013 The Author(s).
Weller M.,University of Zürich |
Weller M.,University of Tübingen |
Gorlia T.,European Organisation for Research and Treatment of Cancer |
Cairncross J.G.,University of Calgary |
And 12 more authors.
Neurology | Year: 2011
Objective: This analysis was performed to assess whether antiepileptic drugs (AEDs) modulate the effectiveness of temozolomide radiochemotherapy in patients with newly diagnosed glioblastoma. Methods: The European Organization for Research and Treatment of Cancer (EORTC) 26981- 22981/National Cancer Institute of Canada (NCIC) CE.3 clinical trial database of radiotherapy (RT) with or without temozolomide (TMZ) for newly diagnosed glioblastoma was examined to assess the impact of the interaction between AED use and chemoradiotherapy on survival. Data were adjusted for known prognostic factors. Results: When treatment began, 175 patients (30.5%) were AED-free, 277 (48.3%) were taking any enzyme-inducing AED (EIAED) and 135 (23.4%) were taking any non-EIAED. Patients receiving valproic acid (VPA) only had more grade 3/4 thrombopenia and leukopenia than patients without an AED or patients taking an EIAED only. The overall survival (OS) of patients who were receiving an AED at baseline vs not receiving any AED was similar. Patients receiving VPA alone (97 [16.9%]) appeared to derive more survival benefit from TMZ/RT (hazard ratio [HR] 0.39, 95% confidence interval [CI] 0.24-0.63) than patients receiving an EIAED only (252 [44%]) (HR 0.69, 95% CI 0.53-0.90) or patients not receiving any AED (HR 0.67, 95% CI 0.49-0.93). Conclusions: VPA may be preferred over an EIAED in patients with glioblastoma who require an AED during TMZ-based chemoradiotherapy. Future studies are needed to determine whether VPA increases TMZ bioavailability or acts as an inhibitor of histone deacetylases and thereby sensitizes for radiochemotherapy in vivo. Copyright © 2011 by AAN Enterprises, Inc.
PubMed | University of Bristol, Ospedale Bellaria, Netherlands Cancer Institute, University of Lausanne and 15 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016
EORTC 26082 assessed the activity of temsirolimus in patients with newly diagnosed glioblastoma harboring an unmethylated O6 methylguanine-DNA-methyltransferase (MGMT) promoter.Patients (n = 257) fulfilling eligibility criteria underwent central MGMT testing. Patients with MGMT unmethylated glioblastoma (n = 111) were randomized 1:1 between standard chemo-radiotherapy with temozolomide or radiotherapy plus weekly temsirolimus (25 mg). Primary endpoint was overall survival at 12 months (OS12). A positive signal was considered >38 patients alive at 12 months in the per protocol population. A noncomparative reference arm of 54 patients evaluated the assumptions on OS12 in a standard-treated cohort of patients. Prespecified post hoc analyses of markers reflecting target activation were performed.Both therapies were administered per protocol with a median of 13 cycles of maintenance temsirolimus. Median age was 55 and 58 years in the temsirolimus and standard arms, the WHO performance status 0 or 1 for most patients (95.5%). In the per protocol population, 38 of 54 patients treated with temsirolimus reached OS12. The actuarial 1-year survival was 72.2% [95% confidence interval (CI), 58.2-82.2] in the temozolomide arm and 69.6% (95% CI, 55.8-79.9) in the temsirolimus arm [hazard ratio (HR) 1.16; 95% CI, 0.77-1.76; P = 0.47]. In multivariable prognostic analyses of clinical and molecular factors, phosphorylation of mTORSer2448 in tumor tissue (HR 0.13; 95% CI, 0.04-0.47; P = 0.002), detected in 37.6%, was associated with benefit from temsirolimus.Temsirolimus was not superior to temozolomide in patients with an unmethylated MGMT promoter. Phosphorylation of mTORSer2448 in the pretreatment tumor tissue may define a subgroup benefitting from mTOR inhibition. Clin Cancer Res; 22(19); 4797-806. 2016 AACR.
Solda F.,Neuro oncology Unit |
Wharram B.,Neuro oncology Unit |
De Ieso P.B.,Neuro oncology Unit |
De Ieso P.B.,University College London |
And 6 more authors.
Radiotherapy and Oncology | Year: 2013
Purpose To assess long term efficacy of fractionated stereotactic radiotherapy (fSRT) in the treatment of benign intracranial meningiomas. Materials and methods Retrospective study of 222 patients with histologically confirmed (58%) and unverified presumed (42%) grade I intracranial meningioma treated with fSRT in a single institution to doses of 50-55 Gy in 30-33 fractions. Results At a median follow-up of 43 months (range 3-144) the 5 and 10 years local control (LC) were 93% and 86%. Patients with tumors involving the optic nerve (42 patients) and patients with cavernous sinus/parasellar region meningiomas (78 patients) had 5 and 10 years LC of 100%. The 5 and 10 years survival probabilities were 93% and 84%. On multivariate analysis gender and tumor site were independent predictors of LC. Worsening of pre-existing cranial nerve deficit occurred in 8 (3.5%) and onset of new deficit in 1 (0.5%) patient. Two patients with optic nerve sheath meningioma (1%) developed radiation retinopathy. There were no cases of radiation necrosis or second brain tumors. Conclusion fSRT achieves excellent medium and long term tumor control with minimal morbidity particularly in patients with benign meningiomas involving the parasellar region and the optic nerves and questions the role of other treatment modalities for tumors at these locations. © 2013 Elsevier Ireland Ltd. All rights reserved.
Yust-Katz S.,Neuro Oncology Unit |
Yust-Katz S.,Tel Aviv University |
Mandel J.J.,Baylor College of Medicine |
Wu J.,University of Houston |
And 7 more authors.
Journal of Neuro-Oncology | Year: 2015
The risk of venous thromboembolism (VTE) is high for patients with brain tumors (11–20 %). Glioblastoma (GBM) patients, in particular, have the highest risk of VTE (24–30 %). The Khorana scale is the most commonly used clinical scale to evaluate the risk of VTE in cancer patients but its efficacy in patients with GBM remains unclear. The aim of this study is to estimate the frequency of VTE in GBM patients and identify potential risk factors for the development of VTE during adjuvant chemotherapy. Furthermore, we intend to examine whether the Khorana scale accurately predicts the risk of VTE in GBM patients. We retrospectively reviewed the medical records of GBM patients treated at MD Anderson during the years 2005–2011. The study cohort included 440 patients of which 64 (14.5 %) developed VTE after the start of adjuvant treatment. The median time to develop VTE was 6.5 months from the start of adjuvant treatment. On multivariate analysis male sex, BMI ≥ 35, KPS ≤ 80, history of VTE and steroid therapy were significantly associated with the development of VTE. The Khorana scale was found to be an invalid VTE predictive model in GBM patients due to poor specificity. Of the 64 patients who developed a VTE, 36 were treated with anticoagulation, 2 with an IVC filter, and 21 with both. Complications (intracranial hemorrhage, bleeding in other organs and thrombocytopenia) secondary to anticoagulation were reported in 16 % (n = 10). VTE is common in patients with GBM. Our results did not validate the Khorana scale in GBM patients. Additional studies identifying which GBM patients are at highest risk for VTE are needed to enable further evaluation of VTE preventive measures in this selected group. © 2015, Springer Science+Business Media New York.
Powell C.,Neuro oncology Unit |
Micallef C.,National Hospital for Neurology and Neurosurgery |
Gonsalves A.,Neuro oncology Unit |
Wharram B.,Neuro oncology Unit |
And 3 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2011
Purpose: To determine the incidence and predictive factors for the development of hydrocephalus in patients with acoustic neuromas (AN) treated with fractionated stereotactic radiotherapy. Patients and Methods: Seventy-two patients with AN were treated with fractionated stereotactic radiotherapy between 1998 and 2007 (45-50 Gy in 25-30 fractions over 5 to 6 weeks). The pretreatment MRI scan was assessed for tumor characteristics and anatomic distortion independently of subsequent outcome and correlated with the risk of hydrocephalus. Results: At a median follow-up of 49 months (range, 1-120 months), 5-year event-free survival was 95%. Eight patients (11%) developed hydrocephalus within 19 months of radiotherapy, which was successfully treated. On univariate analysis, pretreatment factors predictive of hydrocephalus were maximum diameter (p = 0.005), proximity to midline (p = 0.009), displacement of the fourth ventricle (p = 0.02), partial effacement of the fourth ventricle (p < 0.001), contact with the medulla (p = 0.005), and more brainstem structures (p = 0.004). On multivariate analysis, after adjusting for fourth ventricular effacement, no other variables remained independently associated with hydrocephalus formation. Conclusions: Fractionated stereotactic radiotherapy results in excellent tumor control of AN, albeit with a risk of developing hydrocephalus. Patients at high risk, identified as those with larger tumors with partial effacement of the fourth ventricle before treatment, should be monitored more closely during follow-up. It would also be preferable to offer treatment to patients with progressive AN while the risk of hydrocephalus is low, before the development of marked distortion of fourth ventricle before tumor diameter significantly exceeds 2 cm. © 2011 Elsevier Inc.
Powell C.,Neuro Oncology Unit |
Guerrero D.,Neuro Oncology Unit |
Sardell S.,Neuro Oncology Unit |
Cumins S.,Neuro Oncology Unit |
And 6 more authors.
Radiotherapy and Oncology | Year: 2011
Background and purpose: To characterise the incidence, pattern and severity of post cranial radiotherapy somnolence and to identify factors predictive of frequency and severity. Materials and methods: Seventy consecutive patients receiving radical cranial irradiation were prospectively assessed for somnolence at baseline, during and up to 10 weeks following radiotherapy using five variables scored on a visual analogue scale (VAS) and the Littman scale. Fatigue was measured using the FACT-G score and quality of life using the EORTC QLQC30+3 with the brain tumour module questionnaire. Results: Ninety percent of patients experienced ≥grade 1 somnolence (Littman score) and this correlated with VAS scores (r = 0.456, p < 0.001). The score increased from 3 to 12 weeks (p < 0.001) with a peak at the end of treatment and improvement 6 weeks later. None of the patient, disease or treatment characteristics analysed were predictive for the development or the severity of somnolence. Conclusions: The majority of patients experience some degree of somnolence following radical radiotherapy for primary brain tumour and this follows a clear pattern during and after treatment. While there are no clear predictors of severity, the pattern described allows for provision of information for patients and carers to minimise the distress the syndrome may cause. © 2011 Elsevier Ltd. All rights reserved.
Solda F.,Neuro Oncology Unit |
Wharram B.,Neuro Oncology Unit |
Gunapala R.,Neuro Oncology Unit |
Brada M.,Neuro Oncology Unit |
Brada M.,Oncology and Radiotherapy Institute
Clinical Oncology | Year: 2012
Aims: To assess visual outcome, tumour control and treatment-related morbidity in patients with optic nerve sheath meningiomas (ONSMs) treated with fractionated stereotactic radiotherapy (FSRT). Patients and methods: A retrospective analysis of 45 patients (13 men and 32 women, median age 46 years) with ONSMs (51 optic nerves involved) treated in a single institution between 1997 and 2010 was carried out. FSRT was delivered to a dose of 50 Gy in 30 or 33 fractions as primary treatment in 39 patients and after surgery in six patients. Results: At a median follow-up of 30 months (range 1-13 years), the tumour control in 41 evaluable patients (four were lost to follow-up) was 100% at 5 years with no subsequent local or distant recurrence. Of the 46 evaluable optic nerves treated, 41 had residual vision (38 with impaired vision) before radiotherapy and five were blind in one eye. There was no recovery of vision in any of the blind eyes. Of 41 optic nerves with residual vision, 13 had improvement, 24 remained stable and four deteriorated; two patients (4%) developed radiation retinopathy. One patient developed a central retinal artery occlusion in the untreated eye 10 years after treatment. Conclusion: FSRT is highly effective at controlling the growth of ONSMs with improvement or stabilisation of visual deficit in 89% of the optic nerves retaining some vision, albeit with a small risk of radiation-induced retinopathy. The results support the use of FSRT as an effective approach in the management of ONSM. The lack of functional benefit in patients with severe visual impairment would argue for earlier institution of treatment before complete visual loss is established. © 2012 The Royal College of Radiologists.
PubMed | Neuro oncology Unit
Type: Journal Article | Journal: Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology | Year: 2013
To assess long term efficacy of fractionated stereotactic radiotherapy (fSRT) in the treatment of benign intracranial meningiomas.Retrospective study of 222 patients with histologically confirmed (58%) and unverified presumed (42%) grade I intracranial meningioma treated with fSRT in a single institution to doses of 50-55Gy in 30-33 fractions.At a median follow-up of 43months (range 3-144) the 5 and 10years local control (LC) were 93% and 86%. Patients with tumors involving the optic nerve (42 patients) and patients with cavernous sinus/parasellar region meningiomas (78 patients) had 5 and 10years LC of 100%. The 5 and 10years survival probabilities were 93% and 84%. On multivariate analysis gender and tumor site were independent predictors of LC. Worsening of pre-existing cranial nerve deficit occurred in 8 (3.5%) and onset of new deficit in 1 (0.5%) patient. Two patients with optic nerve sheath meningioma (1%) developed radiation retinopathy. There were no cases of radiation necrosis or second brain tumors.fSRT achieves excellent medium and long term tumor control with minimal morbidity particularly in patients with benign meningiomas involving the parasellar region and the optic nerves and questions the role of other treatment modalities for tumors at these locations.
PubMed | Mayo Medical School and Neuro Oncology Unit
Type: | Journal: Handbook of clinical neurology | Year: 2016
Anaplastic oligodendrogliomas have long attracted interest because of their sensitivity to chemotherapy, in particular in the subset of 1p/19q co-deleted tumors. Recent molecular studies have shown that all 1p/19q co-deleted tumors have IDH mutations and most of them also have TERT mutations. Because of the presence of similar typical genetic alterations in astrocytoma and glioblastoma, the current trend is to diagnose these tumors on the basis of their molecular profile. Further long-term follow-up analysis of both EORTC and RTOG randomized studies on (neo)adjuvant procarbazine, lomustine, vincristine (PCV) chemotherapy have shown that adjuvant chemotherapy indeed improves outcome, and this is now standard of care. It is also equally clear that benefit to PCV chemotherapy is not limited to the 1p/19q co-deleted cases; potential other predictive factors are IDH mutations and MGMT promoter methylation. Moreover, a recent RTOG study on low-grade glioma also noted an improved outcome after adjuvant PCV chemotherapy, thus making (PCV) chemotherapy now standard of care for all 1p/19q co-deleted tumors regardless of grade. It remains unclear whether temozolomide provides the same survival benefit, as no data from well-designed clinical trials on adjuvant temozolomide in this tumor type are available. Another question that remains is whether one can safely leave out radiotherapy as part of initial treatment to avoid cognitive side-effects of radiotherapy. The current data suggest that delaying radiotherapy and treatment with chemotherapy only may be detrimental for overall survival.