Leptomeningeal metastasis from solid tumours: EANO-ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up

These joint European Association of Neuro-Oncology (EANO)­European Society for Medical Oncology (ESMO) recommendations for the diagnosis and treatment of leptomeningeal metastasis (LM) from solid tumours provide an update of the first joint EANO­ESMO guideline1 and complement the EANO­ESMO guideline on brain metastasis from solid tumours.2 LM is defined as the spread of tumour cells within the leptomeninges and the subarachnoid space. The present recommendations address LM from extra-central nervous system (CNS) solid tumours, but do not address LM from primary brain tumours, lymphoma or leukaemia. The recommendations cover diagnosis, treatment and follow-up, but do not cover the differential diagnosis, treatment-related adverse events (AEs) or supportive or palliative care in detail. The authors propose diagnostic criteria and assign levels of certainty to the diagnosis of LM in order to provide guidance regarding when to treat versus when to intensify diagnostic efforts and which patients to include in clinical trials. The authors also provide a pragmatic treatment algorithm based on LM subtypes. Supporting evidence for this guideline focuses on LM-specific data with reference to the EANO­ESMO guideline on brain metastasis from solid tumours2 when LM-specific data are not available. Given the low level of evidence available, recommendations are often based on expert opinion and consensus rather than on evidence from informative clinical trials. Still, these EANO­ESMO multidisciplinary recommendations serve as a valuable source of information for physicians and other health care providers, as well as for patients and relatives.

Thirty years of progress in the management of low-grade gliomas.

This paper reviews 30 years of developments in the area of low-grade gliomas. This includes the changes in diagnostics with the incorporation of 1p/19q and IDH mutations in the diagnostic classifier, the improved surgical techniques, improved delivery of radiotherapy and chemotherapy. More recently, the better understanding of the altered cellular processes has lead to the development of novel drugs that may alter completely alter the management of patients early in the course of their disease.

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.

The meaning of screening: detection of brain metastasis in the adjuvant setting for stage III melanoma.

BACKGROUND: The incidence of melanoma is increasing and 37% of patients with metastatic melanoma eventually have brain metastasis (BM). Currently, there is no consensus on screening for BM in patients with resected stage III melanoma. However, given the high incidence of BM, routine screening magnetic resonance imaging (MRI) of the brain is considered in patients with completely resected stage III melanoma before the start of adjuvant treatment. The aim of this study was to assess the yield of screening for BM in these patients. MATERIALS AND METHODS: A single-center cohort study was carried out in the Erasmus MC, Rotterdam, The Netherlands, a large tertiary referral center for patients with melanoma. Eligible patients with complete resection of stage III melanoma and a screening MRI of the brain, made within 12 weeks after resection and before adjuvant treatment (programmed cell death protein 1 inhibitors, dabrafenib-trametinib), available between 1 August 2018 and 1 January 2021, were included. RESULTS: A total of 202 patients were included. Eighteen (8.9%) of 202 patients had extracranial metastasis at screening. Two (1.1%) of the remaining 184 patients had BM at screening, resulting in a switch from adjuvant treatment to ipilimumab-nivolumab. At a median follow-up of 21.2 months, BM was detected in another 4 (2.4%) of 166 patients who started with adjuvant treatment. CONCLUSIONS: The yield of screening MRI of the brain is low after complete resection of stage III melanoma, before the start of adjuvant treatment. Therefore, routine screening MRI is not recommended in this setting.

A qualitative study on the challenges health care professionals face when caring for adolescents and young adults with an uncertain and/or poor cancer prognosis.

BACKGROUND: Adolescents and young adults (AYAs, aged 18-39 years) with advanced cancer have an increased life expectancy due to improvements and refinements in cancer therapies, resulting in a growing group of AYAs living with an uncertain and/or poor cancer prognosis (UPCP). To date, no studies have examined the difficulties of health care professionals (HCPs) providing care to AYAs with a UPCP. This study aimed to understand the challenges in daily clinical practice experienced by HCPs from different disciplines who provide palliative as well as general care to AYAs with a UPCP. METHODS: HCPs from a variety of backgrounds (e.g. clinical nurse specialists, medical oncologists, neurologists psychologists) were invited for a semi-structured interview. The interviews were transcribed verbatim and analysed using reflexive thematic analysis. Two AYA patients were actively involved as research partners to increase the relevance of the study design and to optimise interpretation of results. RESULTS: Forty-nine HCPs were interviewed. Overall, we found that the threat of premature death within this young patient group increased emotional impact on HCPs and evoked a feeling of unfairness, which was an extra motivation for HCPs to provide the most optimal care possible. We generated four key themes: (i) emotional confrontation (e.g. feeling helplessness and experiencing a greater sense of empathy), (ii) questioning own professional attitude and skills, (iii) navigating uncertainty (e.g. discussing prognosis and end of life) and (iv) obstacles in the health care organisation (e.g. lack of knowledge and clarity about responsibilities). CONCLUSIONS: HCPs experienced unique emotional and practical challenges when providing care to AYAs with a UPCP. The results from this study highlight the need to develop an education module for HCPs treating AYAs with UPCP to increase their own well-being and optimise the delivery of person- and age-adjusted care.

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.

Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

Prognostic value and kinetics of circulating endothelial cells in patients with recurrent glioblastoma randomised to bevacizumab plus lomustine, bevacizumab single agent or lomustine single agent. A report from the Dutch Neuro-Oncology Group BELOB trial.

BACKGROUND: Angiogenesis is crucial for glioblastoma growth, and anti-vascular endothelial growth factor agents are widely used in recurrent glioblastoma patients. The number of circulating endothelial cells (CECs) is a surrogate marker for endothelial damage. We assessed their kinetics and explored their prognostic value in patients with recurrent glioblastoma. METHODS: In this side study of the BELOB trial, 141 patients with recurrent glioblastoma were randomised to receive single-agent bevacizumab or lomustine, or bevacizumab plus lomustine. Before treatment, after 4 weeks and after 6 weeks of treatment, CECs were enumerated. RESULTS: The number of CECs increased during treatment with bevacizumab plus lomustine, but not during treatment in the single-agent arms. In patients treated with lomustine single agent, higher absolute CEC numbers after 4 weeks (log10CEC hazard ratio (HR) 0.41, 95% CI 0.18-0.91) and 6 weeks (log10CEC HR 0.16, 95% CI 0.05-0.56) of treatment were associated with improved overall survival (OS). Absolute CEC numbers in patients receiving bevacizumab plus lomustine or bevacizumab single agent were not associated with OS. CONCLUSION: CEC numbers increased during treatment with bevacizumab plus lomustine but not during treatment with either agent alone, suggesting that this combination induced the greatest vascular damage. Although the absolute number of CECs was not associated with OS in patients treated with bevacizumab either alone or in combination, they could serve as a marker in glioblastoma patients receiving lomustine single agent.

How to use molecular markers when caring for a patient with brain cancer: 1P/19Q as a predictive and prognostic marker in the neuro-oncology clinic.

Although the central role of 1p/19q codeletion in oligodendroglioma was established almost two decades ago, apart from clear prognostic significance the implications for clinical care have been less clear. This has changed with the long-term follow-up analysis of the EORTC and RTOG trials on procarbazine, lomustine, and vincristine (PCV) chemotherapy in anaplastic oligodendroglioma. These have shown that 1p/19q loss in these tumors is predictive of overall survival benefit of the addition of PCV chemotherapy to radiotherapy.

Bortezomib-induced polyneuropathy.

BACKGROUND: Peripheral neuropathy is a frequent side effect of bortezomib chemotherapy. Relatively little is known about the clinical characteristics of this neuropathy, especially with respect to pain. Our aim was to describe the clinical characteristics and course of bortezomib-induced polyneuropathy. METHODS: This is a retrospective cohort study of 39 patients diagnosed with bortezomib-induced polyneuropathy. RESULTS: Pain is the most prominent symptom and 14 of 39 patients suffered from severe pain. More than 50% of our patients used analgesics due to moderate or severe pain. We found no correlation between severity of symptoms of bortezomib-induced polyneuropathy and cumulative dose or dose intensity of bortezomib. Nerve conduction studies did not correlate well with symptom severity. Dose reduction or discontinuation of treatment reduced severity in most cases. CONCLUSION: Painful polyneuropathy is a frequent, dose-limiting side effect of bortezomib with a relatively good prognosis. Careful neurological monitoring of symptoms and timely dose adjustment is important.