Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol.

PURPOSE: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. METHODS: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. RESULTS: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant. CONCLUSION: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

Health-related quality of life after chemotherapy with or without rituximab in primary central nervous system lymphoma patients: results from a randomised phase III study.

BACKGROUND: The impact of rituximab on health-related quality of life (HRQoL) in primary central nervous system lymphoma patients is not well known. We determined the impact of rituximab added to standard high-dose methotrexate-based treatment on HRQoL in patients in a large randomised trial. PATIENTS AND METHODS: Patients from a large phase III trial (HOVON 105/ALLG NHL 24), randomly assigned to receive standard chemotherapy with or without rituximab and followed by 30 Gy whole brain radiotherapy (WBRT) in patients ≤60 years, completed the EORTC QLQ-C30 and QLQ-BN20 questionnaires before and during treatment, and up to 24 months of follow-up or progression. Differences between treatment arms over time in global health status, role functioning, social functioning, fatigue, and motor dysfunction were assessed. Differences ≥10 points were deemed clinically relevant. The effect of WBRT on HRQoL was analysed in irradiated patients. RESULTS: A total of 160/175 patients eligible for the HRQoL study completed at least one questionnaire and were included. Over time, scores improved statistically significantly and were clinically relevant in both arms. Between arms, there were no differences on any scale (range: -3.8 to +4.0). Scores on all scales were improved to a clinically relevant extent at 12 and 24 months compared with baseline in both arms, except for fatigue and motor dysfunction at 12 months (-7.4 and -8.8, respectively). In irradiated patients (n = 59), scores in all preselected scales, except motor dysfunction, remained stable up to 24 months compared with shortly after WBRT, overall mean difference ranging between 0.02 and 4.570. CONCLUSION: Compared with baseline, treatment resulted in improved HRQoL scores. The addition of rituximab to standard chemotherapy did not impact HRQoL over time. WBRT did not result in deterioration of HRQoL in the first 2 years.

Withdrawal of antiepileptic drugs in patients with low grade and anaplastic glioma after long-term seizure freedom: a prospective observational study.

BACKGROUND: When glioma patients experience long-term seizure freedom the question arises whether antiepileptic drugs (AEDs) should be continued. As no prospective studies exist on seizure recurrence in glioma patients after AED withdrawal, we evaluated the decision-making process to withdraw AEDs in glioma patients, and seizure outcome after withdrawal. METHODS: Patients with a histologically confirmed low grade or anaplastic glioma were included. Eligible patients were seizure free ≥ 1 year from the date of last antitumor treatment, or ≥ 2 years since the last seizure when seizures occurred after the end of the last antitumor treatment. Patients and neuro-oncologists made a shared decision on the preferred AED treatment (i.e. AED withdrawal or continuation). Primary outcomes were: (1) outcome of the shared decision-making process and (2) rate of seizure recurrence. RESULTS: Eighty-three patients fulfilled all eligibility criteria. However, in 12/83 (14%) patients, the neuro-oncologist had serious objections to AED withdrawal. Therefore, 71/83 (86%) patients were analyzed; In 46/71 (65%) patients it was decided to withdraw AED treatment. In the withdrawal group, 26% (12/46) had seizure recurrence during follow-up. Seven of these 12 patients (58%) had tumor progression, of which three within 3 months after seizure recurrence. In the AED continuation group, 8% (2/25) of patients had seizure recurrence of which one had tumor progression. CONCLUSION: In 65% of patients a shared decision was made to withdraw AEDs, of which 26% had seizure recurrence. AED withdrawal should only be considered in carefully selected patients with a presumed low risk of tumor progression.

Efficacy of intrathecal chemotherapy in patients with central nervous system involvement of hematological malignancies: a retrospective analysis.

INTRODUCTION: Central nervous system (CNS) involvement, especially involvement of the cerebrospinal fluid (CSF), is common in several haematological malignancies. Intrathecal (IT) chemotherapy can be used to manage CSF involvement. METHODS: Here we evaluated the effectiveness of IT chemotherapy among 80 patients with haematological malignancies and CSF localization who were treated with IT chemotherapy from 2001 to 2012. RESULTS: The majority of patients was diagnosed with diffuse large B-cell lymphoma (26%) or acute lymphoblastic leukaemia/lymphoblastic lymphoma (19%). After first-line IT chemotherapy, which mainly consisted of methotrexate (MTX) and corticosteroids, CSF complete response (CSF CR) was achieved in 76% of patients. 91% reached CSF CR when including second-line IT-chemotherapy. Clinical response was documented in 75%. Although most patients were additionally treated with systemic chemotherapy, response rate did not differ between patients treated with CNS-penetrating and CNS-non-penetrating drugs. CNS progression/relapse occurred in 40% of patients with median progression-free survival of 12.2 months. The median overall survival was 18.3 months; 55% of the patients died during follow-up. CONCLUSIONS: Our analysis shows a high response rate after first-line IT chemotherapy, but also a relatively high progression/relapse percentage.

To be in pain (or not): a computer enables outpatients to inform their physician.

BACKGROUND: In the outpatient oncology clinic, pain management is often inadequate. Incorporating a systematic pain management program into visits is likely to improve this. We implemented an integrated program, including a structured pain assessment, pain treatment protocol and patient education module. In the present study, we investigated whether this intervention improved pain control. PATIENTS AND METHODS: At seven oncology outpatient clinics, patients were asked to register their pain intensity on a touch screen computer. These scores were made available into their electronic medical records. Additionally, a hospital-wide treatment protocol for cancer-related pain and a patient education module were developed. A data warehouse system enabled us to extract patient data from the electronic medical record anonymously and to use them for analysis. The primary outcome of the study was the percentage of patients with moderate to severe pain [current pain (CPI), NRS > 4] measured during 2 weeks at the start and 6 months after implementation. As secondary outcomes, we studied the percentage of pain registrations in specific patient groups and the percentage of patients treated with a curative and a palliative intention with (moderate-severe) pain. Differences were tested with the χ(2) test. RESULTS: During the first 6 months, 3407 of the 4345 patients (78%) registered their pain intensity on the touch screen computer. The percentage of patients with moderate to severe CPI decreased 32% (P = 0.021): from 12.5% at start to 8.5% after 6 months. More patients in the palliative phase than in the curative phase of their disease registered their pain intensity (82% versus 75%, respectively, P < 0.005), and more patients in the palliative phase experienced moderate to severe pain (23% versus 14%, respectively, P < 0.001). CONCLUSION: Pain registration by patients themselves is feasible, provides insight into patients' pain intensity and may improve pain control in outpatients with cancer-related pain. CLINICAL TRIAL NUMBER: Because this is an innovation project and not a primary research project, it has no clinical trial number. The protocol and all materials involved were approved by the Institutional Review Board of the Erasmus MC (MEC-2009-324).

Sagopilone (ZK-EPO, ZK 219477) for recurrent glioblastoma. A phase II multicenter trial by the European Organisation for Research and Treatment of Cancer (EORTC) Brain Tumor Group.

BACKGROUND: 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 AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Human chorionic gonadotropin treatment of anti-Hu-associated paraneoplastic neurological syndromes.

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. METHODS: 15 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. RESULTS: Seven 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.

[Three patients with a paraneoplastic neurological syndrome: the significance of paraneoplastic antibodies]. / Drie patiënten met een paraneoplastisch neurologisch syndroom; de betekenis van paraneoplastische antistoffen.

Establishing the presence of paraneoplastic antibodies is important in identifying an often severe neurological syndrome as paraneoplastic and hence directing the search for an underlying neoplasm. A paraneoplastic neurological syndrome was diagnosed in 3 patients. The first was a 64-year-old woman in whom paraneoplastic encephalomyelitis was diagnosed. The diagnosis was strongly supported by a high titre of serum anti-Hu antibodies, despite three negative biopsies from a mediastinal mass. The patient died of a non-convulsive status epilepticus; autopsy revealed not only paraneoplastic encephalomyelitis but also small-cell lung cancer. The second patient was a 55-year-old woman with metastatic breast cancer. After a three-year period of progressive neurological deterioration, a high titre of anti-CV2/CRMP5 antibodies was detected, on the basis of which the clinical syndrome was diagnosed as paraneoplastic. She received immunotherapy and her condition stabilised. The third patient, a 41-year-old man, presented with severe limbic encephalitis. Biopsy from a paraaortic mass was positive for undifferentiated carcinoma. The patient had a high titre ofanti-Ma2 antibodies and was subsequently tested positive for serum alpha-foetoprotein (AFP) and beta-human-chorionic gonadotrophin (bta-HCG). During chemotherapy for a non seminoma testicular cancer, the limbic encephalitis improved both clinically and radiologically, but the patient died as a result of the toxicity of the treatment.

Corticosteroid use and risk of aneurysmal subarachnoid haemorrhage.

OBJECTIVES: Corticosteroids can induce hypertension and inhibit collagen synthesis in the blood vessel wall. Deficiencies in collagen have been found in intracranial aneurysms. Therefore use of corticosteroids could be a risk factor for intracranial aneurysms and aneurysmal subarachnoid haemorrhage (SAH). We investigated the relationship between the systemic use of corticosteroids in the past and the occurrence of aneurysmal SAH. METHODS: We compared the systemic use of corticosteroids (oral or intravenous) in the past between a consecutive series of 1158 patients with aneurysmal SAH and a control group consisting of 1019 patients diagnosed with a primary central nervous system (CNS) tumour. We discriminated between definite use of corticosteroids defined as use mentioned in the medical record and possible use defined as note in the medical record of a disease that may be treated with corticosteroids. We calculated odds ratios (OR) with corresponding 95% confidence intervals (CI) and adjusted for age and sex by means of logistic regression analyses. RESULTS: Twenty (1.7%, 95% CI 1.1-2.7) of the SAH patients and eight (0.8%, 95% CI 0.3-1.5) of the controls had used systemic corticosteroids (OR: 2.22; 95% CI 0.97-5.05; p-value 0.058; adjusted OR 2.23; 95 % CI 0.97-5.15; p-value 0.059). For definite plus possible use the OR was 1.67 (95% CI 1.09-2.54; p-value 0.016) and the adjusted OR 1.52 (95% CI 0.99-2.33; p-value 0.055). CONCLUSIONS: Patients with aneurysmal SAH more often have used systemic corticosteroids in the past than controls. This may suggest that the use of corticosteroids is a risk factor for aneurysmal SAH.

[Temozolomide in patients with a glioblastoma multiforme: new developments]. / Temozolomide bij patienten met een glioblastoma multiforme: nieuwe ontwikkelingen.

There are new scientific data concerning the treatment of patients with glioblastoma multiforme with concomitant and adjuvant temozolomide following surgery and radiotherapy. Patients have an improved survival rate, especially if they also have a methylated promoter of the methylguanine-DNA-methyltransferase (MGMT) gene. It is advisable to consider treating young patients with primary glioblastoma multiforme who are in good condition with concomitant and adjuvant temozolomide. Efficacy of temozolomide in recurrent glioblastoma multiforme is limited.

Is a "vanishing tumor" always a lymphoma?

The authors report clinical and radiologic characteristics and ultimate diagnosis in 12 patients with a regressing cerebral mass lesion. Primary CNS lymphoma (PCNL) was found in only half of the patients with such a lesion. In patients showing a complete resolution of the enhancing lesion the probability of finding a PCNL is smaller and survival is longer.

Radiotherapy-induced cerebral abnormalities in patients with low-grade glioma.

Abnormalities on CT or MRI and neuropsychological performance in patients with low-grade glioma, with (n = 23) or without (n = 16) prior cerebral radiotherapy, were evaluated. Cerebral atrophy was observed in 14 of 23 patients (61%) treated with prior radiotherapy, and in 1 of 16 patients (6%) without prior radiotherapy. White matter abnormalities were observed in six patients, all of whom were treated with prior radiotherapy. These radiologic cerebral abnormalities correlated with cognitive performance.

[Clinical reasoning and decision making in practice. A man with unilateral attacks of muscular rigidity following neck surgery for a malignant tumor]. / Klinisch denken en beslissen in de praktijk. Een man met eenzijdige aanvalsgewijze spierverstijvingen na een halsoperatie wegens maligniteit.

A 54-year-old man with a history of generalised tonic clonic seizures presented with complaints of daily unilateral stiffening of the limbs, preceded by paraesthesia. Two years before he had been treated with surgery and radiotherapy for a laryngo-pharyngeal carcinoma. Therefore, epilepsy due to intracerebral metastasis was suggested. However, neither CT nor MRI of the brain (with intravenous contrast) showed any abnormalities and the EEG showed no epileptiform discharges. Laboratory tests revealed elevated levels of thyroid-stimulating hormone in the blood, hypocalcaemia, hyperphosphataemia and hypomagnesaemia. In combination with the medical history, tetany was found to be the correct diagnosis. In this patient, tetany was caused by hypoparathyroidism secondary to surgery and radiotherapy in the neck region. He was treated with levothyroxine, magnesium, calcium, and vitamin D and recovered in a few weeks' time. Hypothyroidism and hypoparathyroidism are common complications after treatment (surgery, radiotherapy and/or chemotherapy) for laryngo-pharyngeal carcinoma and other malignancies in the neck region.

[Neurological presentation of non-Hodgkin lymphoma: a diagnostic problem]. / Neurologische presentatie van het non-Hodgkin-lymfoom: een diagnostisch probleem.

In two patients, men aged 69 and 38 years, neurological signs were the first presenting symptoms of systemic non-Hodgkin's lymphoma (NHL). This presentation is uncommon. The patients had focal neurological deficit and elevated serum lactate dehydrogenase (LDH) activity. Neurological manifestations of NHL may be caused by extradural lymphoma or by diffuse leptomeningeal metastasis (meningitis lymphomatosa). A third patient, a woman of 48, had a third form of nervous system involvement, primary cerebral NHL, which is not a metastatic sequel to systemic NHL. Primary neurological presentation of NHL may be difficult to diagnose, particularly in case of prior treatment with corticosteroids.

Higher doses of opioids in patients who need palliative sedation prior to death: cause or consequence?

BACKGROUND: 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. PATIENTS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: These results indicate that IDH1 mutations identify a subgroup of gliomas with an improved survival, but are unrelated to the temozolomide response.