[Show abstract][Hide abstract] ABSTRACT: Background
Epilepsy is common in patients with a glioma. Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment, but may cause side effects and may negatively impact neurocognitive functioning and quality of life. Besides antiepileptic drugs, anti-tumour treatment, which currently consists of surgery, radiotherapy and/or chemotherapy, may contribute to seizure control as well. In glioma patients with seizure freedom after anti-tumour therapy the question emerges whether AEDs should be continued, particularly in the case where anti-tumour treatment has been successful. We propose to explore the possibility of AED withdrawal in glioma patients with long-term seizure freedom after anti-tumour therapy and without signs of tumour progression.Methods/designWe initiate a prospective, observational study exploring the decision-making process on the withdrawal or continuation of AEDs in low-grade and anaplastic glioma patients with stable disease and prolonged seizure freedom after anti-tumour treatment, and the effects of AED withdrawal or continuation on seizure freedom. We recruit participants through the outpatient clinics of three tertiary referral centers for brain tumour patients in The Netherlands. The patient and the treating physician make a shared decision to either withdraw or continue AED treatment. Over a one-year period, we aim to include 100 glioma patients. We expect approximately half of the participants to be willing to withdraw AEDs. The primary outcome measures are: 1) the outcome of the shared-decision making on AED withdrawal or continuation, and decision related arguments, and 2) seizure freedom at 12 months and 24 months of follow-up. We will also evaluate seizure type and frequency in case of seizure recurrence, as well as neurological symptoms, adverse effects related to AED treatment or withdrawal, other anti-tumour treatments and tumour progression.DiscussionThis study addresses two issues that are currently unexplored. First, it will explore the willingness to withdraw AEDs in glioma patients, and second, it will assess the risk of seizure recurrence in case AEDs are withdrawn in this specific patient population. This study aims to contribute to a more tailored AED treatment, and prevent unnecessary and potentially harmful use of AEDs in glioma patients.
[Show abstract][Hide abstract] ABSTRACT: Treatment options for recurrent glioblastoma are scarce, with second-line chemotherapy showing only modest activity against the tumour. Despite the absence of well controlled trials, bevacizumab is widely used in the treatment of recurrent glioblastoma. Nonetheless, whether the high response rates reported after treatment with this drug translate into an overall survival benefit remains unclear. We report the results of the first randomised controlled phase 2 trial of bevacizumab in recurrent glioblastoma.
The Lancet Oncology 07/2014; · 25.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Several lines of evidence suggest a T cell-mediated immune response in paraneoplastic neurological syndromes with anti-Hu antibodies (Hu-PNS). In order to investigate whether suppression of T cell-mediated immune responses in Hu-PNS patients improved their neurological outcome, we performed a prospective open-label, single-arm study on sirolimus.
[Show abstract][Hide abstract] ABSTRACT: The benefit of intrathecal therapy and systemic rituximab on the outcome of diffuse large B-cell lymphoma at risk of central nervous system disease is controversial. Furthermore, the effect of intrathecal treatment and rituximab in diffuse large B-cell and Burkitt lymphoma with occult leptomeningeal disease detected by flow cytometry at diagnosis is unknown. Untreated diffuse large B-cell (n=246) and Burkitt (n=80) lymphoma at clinical risk of central nervous system disease and had pretreatment cerebrospinal fluid analyzed by flow cytometry and and cytology. Spinal fluid involvement was detected by flow cytometry alone (occult) in 33 (13%) diffuse large B-cell and 9 (11%) Burkitt lymphoma patients, and detected by cytology in 11 (4.5%) and 5 (6%) patients, respectively. Diffuse large B-cell lymphoma with occult spinal fluid involvement had poorer survival (p=0.0001) and freedom from central nervous system relapse (p<0.0001) compared to negative cases. Burkitt lymphoma with occult spinal fluid involvement had an inferior freedom from central nervous system relapse (p=0.026) but not survival. The amount of intrathecal chemotherapy was quantitatively associated with survival in diffuse large B-cell lymphoma with (p=0.02) and without (p=0.001) occult spinal fluid involvement. However, progression of systemic disease and not control of central nervous system disease was the principal cause of treatment failure. In diffuse large B-cell lymphoma, systemic rituximab was associated with improved freedom from central nervous system relapse (p=0.003) but not survival. Our results suggest that patients at risk of central nervous system disease should be evaluated by flow cytometry and that intrathecal prophylaxis/therapy is beneficial.
[Show abstract][Hide abstract] ABSTRACT: Primary intracranial germ-cell tumors are rare tumors primarily of adolescence, and literature on this disease in adults is scarce. The available evidence on intracranial germ-cell tumors is reviewed with a focus on adult patients whenever possible, and used to make suggestions for diagnosis and treatment. Diagnostic and treatment algorithms were developed to provide an evidence-based backbone to base treatment on in adult patients with a (suspected) primary intracranial germ-cell tumor.
Journal of Neuro-Oncology 03/2013; · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background. Autologous stem cell transplantation has greatly improved prognosis in systemic recurrent non-Hodgkin lymphoma. However, for systemic lymphoma relapsing in the central nervous system no prospective data are available concerning feasibility and efficacy. Therefore we performed an international multicenter retrospective study of patients with a central nervous system recurrence of systemic lymphoma to assess the outcome of these patients in the era of stem cell transplantation. Design and Methods. We collected clinical and treatment data on patients with a first central nervous system recurrence of systemic lymphoma treated between 2000 and 2010 in one of five centres in four countries. Patient- and treatment-related factors were analyzed and compared descriptively. Primary outcome measures were overall survival and percentage of patients transplanted. Results. We identified 92 patients, with a median age of 59 years and a median Eastern Cooperative Oncology Group/World health Organization performance status of 2, of whom 76% had diffuse large B-cell histology. The majority (79%) was treated with systemic chemotherapy with or without intravenous rituximab. Twenty-seven patients (29%) were transplanted; age and insufficient response to induction chemotherapy were the main reasons for not being transplanted in the remaining 65 patients. Median overall survival was 7 months (95% confidence interval 2.6-11.4); 8 months (95% confidence interval 3.8-5.2) for patients ≤ 65 years. One year survival was 34.8%; of the 27 transplanted patients 62% survived more than 1 year. The Memorial Sloan Kettering Prognostic Index for primary central nervous system lymphoma was prognostic for both achieving transplantation and survival. Conclusions. Despite the availability of autologous stem cell transplantation for patients with central nervous system progression or relapse of systemic lymphoma, prognosis is still poor. Long-term survival is, however, possible and more likely in patients able to undergo stem cell transplantation.
[Show abstract][Hide abstract] ABSTRACT: Low grade gliomas affect predominantly young adults, and have a relatively favorable prognosis compared to grade III and grade IV gliomas. The challenge for an optimal management of these patients is to find the balance between an optimal survival and the preservation of neurological function including cognition. Because all medical treatments may induce side effects, in young and nearly asymptomatic patients the choices can be difficult. This review summarizes the current strategies: a watch-and-wait policy, surgery, chemotherapy, and radiotherapy.
memo - Magazine of European Medical Oncology 09/2012; 5(3):223-227.
[Show abstract][Hide abstract] ABSTRACT: Alternative temozolomide regimens have been proposed to overcome O(6)-methylguanine-DNA methyltransferase mediated resistance. We investigated the efficacy and tolerability of 1 week on/1 week off temozolomide (ddTMZ) regimen in a cohort of patients treated with ddTMZ between 2005 and 2011 for the progression of a glioblastoma during or after chemo-radiation with temozolomide or a recurrence of another type of glioma after radiotherapy and at least one line of chemotherapy. Patients received ddTMZ at 100-150 mg/m(2)/d (days 1-7 and 15-21 in cycles of 28-days). All patients had a contrast enhancing lesion on MRI and the response was assessed by MRI using the RANO criteria; complete and partial responses were considered objective responses. Fifty-three patients were included. The median number of cycles of ddTMZ was 4 (range 1-12). Eight patients discontinued chemotherapy because of toxicity. Two of 24 patients with a progressive glioblastoma had an objective response; progression free survival at 6 months (PFS-6) in glioblastoma was 29%. Three of the 16 patients with a recurrent WHO grade 2 or 3 astrocytoma or oligodendroglioma or oligo-astrocytoma without combined 1p and 19q loss had an objective response and PFS-6 in these patients was 38%. Four out of the 12 evaluable patients with a recurrent WHO grade 2 or 3 oligodendroglioma or oligo-astrocytoma with combined 1p and 19q loss had an objective response; PFS-6 in these patients was 62%. This study indicates that ddTMZ is safe and effective in recurrent glioma, despite previous temozolomide and/or nitrosourea chemotherapy. Our data do not suggest superior efficacy of this schedule as compared to the standard day 1-5 every 4 weeks schedule.
Journal of Neuro-Oncology 03/2012; 108(1):195-200. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The increasing use of hematopoietic stem-cell transplantation (HSCT) for the treatment of leukemia and lymphoma has subjected
patients with these diseases to a variety of neurologic complications, some of which have been described only in the transplant
population. Neurologic complications differ in patients receiving autologous versus allogenic HSCT, and the spectrum of possible
complications changes during the course of HSCT. Neurologic complications of HSCT are frequently serious, difficult to diagnose
and treat, and a source of considerable morbidity and mortality. Knowledge of possible explanations for neurologic symptoms
and signs in patients receiving HSCT can accelerate an accurate diagnosis and timely therapeutic intervention.
[Show abstract][Hide abstract] ABSTRACT: Palliative sedation (PS) is necessary in a significant percentage of patients dying on an acute palliative care unit (PCU). Common indications are terminal restlessness, pain and dyspnoea. On our PCU, terminal restlessness was the main indication for PS but pain was the most prevalent symptom during admission. Because delirium is often drug induced in terminal cancer patients and opioids are amongst the most frequently implicated drugs, we hypothesised that the underlying pain problem and its treatment might have been related to the need for sedation.
To test this hypothesis, we did a retrospective analysis on the use of medication with potential cognitive side-effects, focusing on analgesics, in 68 patients who died on the PCU after PS and 89 patients who died without PS.
Ultimately sedated patients used opioids in significantly higher doses; they were more often treated with a rotation to another opioid and with amitriptyline. The dose of opioids used at various time points between admission and death was strongly related to the probability of PS.
Our findings support the hypothesis that, although pain was not the main indication for PS, pain and its treatment might have been primarily related to the need for palliative sedation in this patient cohort.
European journal of cancer (Oxford, England: 1990) 07/2011; 47(15):2341-6. · 4.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sagopilone (ZK 219477), a lipophylic and synthetic analog of epothilone B, that crosses the blood-brain barrier has demonstrated preclinical activity in glioma models.
Patients with first recurrence/progression of glioblastoma were eligible for this early phase II and pharmacokinetic study exploring single-agent sagopilone (16 mg/m(2) over 3 h every 21 days). Primary end point was a composite of either tumor response or being alive and progression free at 6 months. Overall survival, toxicity and safety and pharmacokinetics were secondary end points.
Thirty-eight (evaluable 37) patients were included. Treatment was well tolerated, and neuropathy occurred in 46% patients [mild (grade 1) : 32%]. No objective responses were seen. The progression-free survival (PFS) rate at 6 months was 6.7% [95% confidence interval (CI) 1.3-18.7], the median PFS was just over 6 weeks, and the median overall survival was 7.6 months (95% CI 5.3-12.3), with a 1-year survival rate of 31.6% (95% CI 17.7-46.4). Maximum plasma concentrations were reached at the end of the 3-h infusion, with rapid declines within 30 min after termination.
No evidence of relevant clinical antitumor activity against recurrent glioblastoma could be detected. Sagopilone was well tolerated, and moderate-to-severe peripheral neuropathy was observed in despite prolonged administration.
Annals of Oncology 02/2011; 22(9):2144-9. · 7.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Only a few studies examined the effect of temozolomide (TMZ) in recurrent low-grade astrocytoma (LGA) after surgery, none of which included a homogeneous and sufficiently sized group of patients with progression after radiotherapy (RT). We evaluated a cohort of 58 patients treated with TMZ for progression after RT of a previous LGA and investigated the relation between outcome and mutations in the IDH1, IDH2, and TP53 genes, O⁶-methylguanine-methyltransferase (MGMT) promoter methylation, trisomy of chromosome 7, and loss of chromosomes 1p and 19q. All patients received first-line TMZ 200 mg/m²/day on days 1-5 every 4 weeks for a progressive LGA with a contrast-enhancing lesion on MRI after RT. Six months progression-free survival (PFS) was 67%, and the median overall survival was 14 months. An objective response was obtained in 54%. TP53 mutations and loss of chromosome 19q showed a borderline association with PFS, but none of the other molecular characteristics were correlated with the outcome to TMZ. Both a methylated MGMT promoter gene and IDH1 mutations were found in 86% of the tumor samples. A correlation was found between IDH1 mutations and MGMT promoter methylation (P < .001). Neither MGMT promoter methylation nor IDH1 mutations correlated with PFS, but the interval between the very first symptom of the LGA and the start of the TMZ was significantly longer in the patients with IDH1 mutations (P = .01) and a methylated MGMT promoter (P = .02). We conclude that MGMT promoter methylation and IDH1 mutations seem to predict survival from the time of diagnosis, but not PFS to TMZ.
[Show abstract][Hide abstract] ABSTRACT: Until some 15 years ago, the diagnosis of an anaplastic oligodendroglioma (AOD) or anaplastic oligoastrocytoma (AOA) was merely
a pathological entity. The only clinically relevant meaning of this histological diagnosis was the observation that in general
the prognosis of OD was better than that of astrocytic tumors of similar grade. This changed with the recognition of the marked
sensitivity of these tumors to procarbazine, lomustine, and vincristine (PCV) chemotherapy [1,2]. A major step forward was
the identification of the combined loss of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) as the
typical genetic lesions of OD, followed by the recognition that in particular these 1p/19q co-deleted tumors have an excellent
response to chemotherapy [3–5]. It is now clear that AOD and AOA with this combined loss of 1p/19q do not only have a better
response to chemotherapy, but they also have a more indolent clinical behavior and a longer lasting response to radiotherapy
KeywordsAnaplastic oligodendroglioma-Anaplastic oligoastrocytoma-1p/19q co-deletion-
[Show abstract][Hide abstract] ABSTRACT: Elderly patients with primary central nervous ystem lymphoma (PCNSL) do not tolerate treatment with combined radio-chemotherapy well because of leuco-encephalopathy; they are usually treated initially with chemotherapy or radiotherapy alone. Little is known about the efficacy and toxicity of these treatments outside clinical studies. This study was a retrospective analysis of all patients aged 60 years or over who were admitted with PCNSL to one of five Dutch centers between 1998 and 2007. A total of 74 patients were identified. Twenty-nine were treated with radiotherapy only (Group A), in 36 the intended treatment was chemotherapy alone (Group B), and nine were planned to receive chemotherapy followed by radiotherapy (Group C). Median overall survival was 20 months; 4 months in patients with a Karnofsky performance status (KPS) <70, 25 months in patients with a KPS ≥ 70 (P < 0·001). Treatment modality was not an independent prognostic factor. Forty patients were treated with methotrexate 3 g/m(2) : there were two toxic deaths. Ten patients discontinued chemotherapy because of toxicity. Delayed encephalopathy was reported in 10 patients. In conclusion, community hospitals still frequently utilize whole brain radiotherapy in elderly PCNSL patients, though a majority tolerates chemotherapy well. Performance status was the most important variable determining prognosis. Short and long term toxicities must be weighed against possible clinical benefits of each treatment, making treatment decisions a highly individualized process.
British Journal of Haematology 10/2010; 151(2):179-84. · 4.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Paraneoplastic neurological syndromes associated with anti-Hu antibodies (Hu-PNS) are mediated by a T-cell immune response that is directed against the Hu antigens. In pregnancy, many Th1-mediated autoimmune diseases such as rheumatoid arthritis and multiple sclerosis regress. We hypothesised that this decreased disease activity during pregnancy may be related to high human chorionic gonadotropin (hCG) levels.Methods15 Hu-PNS patients were treated in a prospective, uncontrolled and unblinded trial with 10 000 IU daily of hCG administered by intramuscular injection during 12 weeks. Primary outcome measures were functional improvement defined as a decrease of one or more points on the modified Rankin Scale (mRS) or stabilisation in patients with mRS score ≤3 and improvement of neurological impairment assessed with the Edinburgh Functional Impairment Tests (EFIT). Secondary end points included the change in activities of daily living as evaluated using the Barthel Index.ResultsSeven of 15 patients (47%) improved on the mRS or stabilised at mRS score ≤3. Four patients (27%) showed significant improvement of neurological impairment as indicated by an overall Edinburgh Functional Impairment Tests score of ≥1 point. Five patients improved on the Barthel Index (33%).Conclusion
Comparison with previous studies suggests that hCG may have immunomodulatory activity and may modify the course of Hu-PNS, although well-established confounding factors may have contributed in this uncontrolled trial.
Journal of neurology, neurosurgery, and psychiatry 01/2010; 81(12):1341-1344. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been implicated in tumorigenesis of gliomas. Patients with high-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival, but it is unknown if this improved survival also holds for low-grade astrocytoma and whether these mutations predict outcome to specific treatment.
We retrospectively investigated the correlation of IDH1 and IDH2 mutations with overall survival and response to temozolomide in a cohort of patients with dedifferentiated low-grade astrocytomas treated with temozolomide at the time of progression after radiotherapy.
IDH1 mutations were present in 86% of the 49 progressive astrocytomas. No mutations in IDH2 were found. Presence of IDH1 mutations were early events and significantly improved overall survival (median survival 48 vs 98 months), but did not affect outcome of temozolomide treatment.
These results indicate that IDH1 mutations identify a subgroup of gliomas with an improved survival, but are unrelated to the temozolomide response.