•Despite limited evidence, lomustine has emerged as standard of care for glioblastoma world-wide.•Its activity may be restricted to patients with MGMT promoter-methylated tumors.•Lomustine is ...considered the most active compound of the PCV polychemotherapy protocol.
Glioblastomas are the most common malignant primary intrinsic brain tumors. Their incidence increases with age, and males are more often affected. First-line management includes maximum safe surgical resection followed by involved-field radiotherapy plus concomitant and six cycles of maintenance temozolomide chemotherapy. Standards of care at recurrence are much less well defined. Minorities of patients are offered second surgery or re-irradiation, but data on a positive impact on survival from randomized trials are lacking. The majority of patients who are eligible for salvage therapy receive systemic treatment, mostly with nitrosourea-based regimens or, depending on availability, bevacizumab alone or in various combinations. In clinical trials, lomustine alone has been increasingly used as a control arm, assigning this drug a standard-of-care position in the setting of recurrent glioblastoma. Here we review the activity of lomustine in the treatment of diffuse gliomas of adulthood in various settings. The most compelling data for lomustine stem from three randomized trials when lomustine was combined with procarbazine and vincristine as the PCV regimen in the newly diagnosed setting together with radiotherapy; improved survival with PCV was restricted to patients with isocitrate dehydrogenase-mutant tumors. No other agent with the possible exception of regorafenib has shown superior activity to lomustine in recurrent glioblastoma, but activity is largely restricted to patients with tumors with O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Hematological toxicity, notably thrombocytopenia often limits adequate exposure.
Summary Patients with glioma present with complex palliative care needs throughout their disease trajectory. The life-limiting nature of gliomas and the presence of specific symptoms related to ...neurological deterioration necessitate an appropriate and early palliative care approach. The multidisciplinary palliative care task force of the European Association of Neuro-Oncology did a systematic review of the available scientific literature to formulate the best possible evidence-based recommendations for the palliative care of adult patients with glioma, with the aim to reduce symptom burden and improve the quality of life of patients and their caregivers, particularly in the end-of-life phase. When recommendations could not be made because of the scarcity of evidence, the task force either used evidence from studies of patients with systemic cancer or formulated expert opinion. Areas of palliative care that currently lack evidence and thus deserve attention for further research are fatigue, disorders of behaviour and mood, interventions for the needs of caregivers, and timing of advance care planning.
In response to major changes in diagnostic algorithms and the publication of mature results from various large clinical trials, the European Association of Neuro-Oncology (EANO) recognized the need ...to provide updated guidelines for the diagnosis and management of adult patients with diffuse gliomas. Through these evidence-based guidelines, a task force of EANO provides recommendations for the diagnosis, treatment and follow-up of adult patients with diffuse gliomas. The diagnostic component is based on the 2016 update of the WHO Classification of Tumors of the Central Nervous System and the subsequent recommendations of the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy - Not Officially WHO (cIMPACT-NOW). With regard to therapy, we formulated recommendations based on the results from the latest practice-changing clinical trials and also provide guidance for neuropathological and neuroradiological assessment. In these guidelines, we define the role of the major treatment modalities of surgery, radiotherapy and systemic pharmacotherapy, covering current advances and cognizant that unnecessary interventions and expenses should be avoided. This document is intended to be a source of reference for professionals involved in the management of adult patients with diffuse gliomas, for patients and caregivers, and for health-care providers.
Summary Background Brain metastases occur in 30–50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy ...(WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer. Methods In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m2 , orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov , number NCT00967031. Findings Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2–27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1–79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred. Interpretation The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted. Funding GlaxoSmithKline-France and UNICANCER.
Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to ...lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma.
We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O
-methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival.
A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval CI, 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health-related quality of life nor neurocognitive function. The MGMT status was prognostic.
Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann-La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939 ; Eudra-CT number, 2010-023218-30 .).
Patients with HER2-positive breast cancer (HER2 + BC) develop central nervous system metastases twice as often as patients with luminal HER2-negative breast cancer. Leptomeningeal progression results ...in a drastically altered prognosis with limited therapeutic options. This phase II study was conducted to assess the efficacy of intrathecal (IT) trastuzumab in HER2 + BC patients with leptomeningeal metastasis (LM), based on a phase I dose-escalation study that had determined the recommended weekly dose of 150 mg for phase II.
Eligible patients received weekly administrations of 150 mg of IT trastuzumab. The primary endpoint was clinical neurologic progression-free survival (LM-related-PFS) after 8 weeks. Overall survival (OS), toxicities, and quality of life (QoL) were secondary endpoints.
Among the 19 enrolled patients, 16 (84%) had concomitant brain metastases, 15 of them had received prior radiotherapy to the brain. All patients had received at least one line of systemic anti-HER2 therapy. After 8 weeks, 14 patients (74%) were free of neurological progression. The median LM-related-PFS was 5.9 months and the median OS was 7.9 months. According to the QLQ-C30 and BN20 scales, the global health-related QoL status seemed preserved and no toxicity above grade 3 was observed.
Conducting studies on patients with LM poses significant challenges and ethical dilemmas inherent to this population. Despite some limits, this phase II study's findings in terms of clinical neurologic response and QoL's control confirms weekly administration of 150 mg of IT trastuzumab as a valuable option for HER + BC patients with LM and support the interest for further investigations.
Leptomeningeal metastases (LM) currently lack standardization with respect to response assessment. A Response Assessment in Neuro-Oncology (RANO) working group with expertise in LM developed a ...consensus proposal for evaluating patients treated for this disease. Three basic elements in assessing response in LM are proposed: a standardized neurological examination, cerebral spinal fluid (CSF) cytology or flow cytometry, and radiographic evaluation. The group recommends that all patients enrolling in clinical trials undergo CSF analysis (cytology in all cancers; flow cytometry in hematologic cancers), complete contrast-enhanced neuraxis MRI, and in instances of planned intra-CSF therapy, radioisotope CSF flow studies. In conjunction with the RANO Neurological Assessment working group, a standardized instrument was created for assessing the neurological exam in patients with LM. Considering that most lesions in LM are nonmeasurable and that assessment of neuroimaging in LM is subjective, neuroimaging is graded as stable, progressive, or improved using a novel radiological LM response scorecard. Radiographic disease progression in isolation (ie, negative CSF cytology/flow cytometry and stable neurological assessment) would be defined as LM disease progression. The RANO LM working group has proposed a method of response evaluation for patients with LM that will require further testing, validation, and likely refinement with use.
Meningiomas are the most frequent nonglial primary brain tumors and represent about 30% of brain tumors. Usually, diagnosis and treatment planning are based on neuroimaging using mainly MRI or, ...rarely, CT. Most common treatment options are neurosurgical resection and radiotherapy (eg, radiosurgery, external fractionated radiotherapy). For follow-up after treatment, a structural imaging technique such as MRI or CT is used. However, these structural imaging modalities have limitations, particularly in terms of tumor delineation as well as diagnosis of posttherapeutic reactive changes. Molecular imaging techniques such as PET can characterize specific metabolic and cellular features which may provide clinically relevant information beyond that obtained from structural MR or CT imaging alone. Currently, the use of PET in meningioma patients is steadily increasing. In the present article, we provide recommendations for the use of PET imaging in the clinical management of meningiomas based on evidence generated from studies being validated by histology or clinical course.
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