Roberta Rudà

PCV chemotherapy for recurrent oligodendrogliomas and oligoastrocytomas.

OBJECTIVE The role of chemotherapy in the treatment of low-grade oligodendrogliomas and oligoastrocytomas is still unclear. A Phase II study was conducted to determine the benefits and toxicity of the procarbazine, lomustine, and vincristine (PCV) regimen in patients with low-grade oligodendrogliomas and oligoastrocytomas recurrent after surgery alone or surgery with radiotherapy. METHODS Patients with both enhancing and nonenhancing tumors were treated with up to six cycles of standard PCV, and response was evaluated by conventional criteria based on computed tomography or magnetic resonance imaging. RESULTS Sixteen of 26 patients (62%) responded to PCV: 3 (12%) experienced complete response, 13 (50%) experienced partial response, 8 (31%) had stable disease, and 2 (8%) had progressive disease. All symptomatic patients who responded and three with stable disease improved in seizure frequency, lateralizing signs, and symptoms of intracranial hypertension. The response rate for patients with enhancing lesions revealed by computed tomography or magnetic resonance imaging (74%) was significantly higher than that of patients with nonenhancing lesions (29%) (P < 0.05). Both oligodendrogliomas and oligoastrocytomas responded to PCV, with complete responses occurring in association with pure tumors only. The median time to tumor progression of all 26 patients was 24 months and was significantly longer for those with oligodendrogliomas compared with those with oligoastrocytomas (32 versus 12 mo) (P < 0.001). Chemotherapy was well tolerated, with mild hematological toxicity and rare skin rashes being the most frequent sequelae. CONCLUSION These results suggest that chemotherapy with PCV is effective in the treatment of recurrent low-grade oligodendrogliomas and oligoastrocytomas.

Brain metastases: current management and new developments.

Purpose of review To review the state-of-the-art and new developments in the management of patients with brain metastases. Recent findings Treatment decisions are based on prognostic factors to maximize neurologic function and survival, while avoiding unnecessary therapies. Whole-brain radiotherapy (WBRT) is the treatment of choice for patients with unfavorable prognostic factors. Stereotactic radiosurgery (SRS) or surgery is indicated for patients with favorable prognostic factors and limited brain disease. In single brain metastasis, the addition of either stereotactic radiosurgery or surgery to WBRT improves survival. The omission of WBRT after surgery or radiosurgery results in a worse local and distant control, though it does not affect survival. The incidence of neurocognitive deficits in long-term survivors after WBRT remains to be defined. New approaches to avoid cognitive deficits following WBRT are being investigated. The role of chemotherapy is limited. Molecularly targeted therapies are increasingly employed. Prophylaxis with WBRT is the standard in small-cell lung cancer. Summary Many questions need future trials: the usefulness of new radiosensitizers; the role of local treatments after surgery; and the impact of molecularly targeted therapies on subgroups of patients with specific molecular profiles. Quality of life and cognitive functions are recognized as major endpoints in clinical trials.

Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments

Seizures represent a common symptom in low-grade gliomas; when uncontrolled, they significantly contribute to patient morbidity and negatively impact quality of life. Tumor location and histology influence the risk for epilepsy. The pathogenesis of tumor-related epilepsy is multifactorial and may differ among tumor histologies (glioneuronal tumors vs diffuse grade II gliomas). Gross total resection is the strongest predictor of seizure freedom in addition to clinical factors, such as preoperative seizure duration, type, and control with antiepileptic drugs (AEDs). Epilepsy surgery may improve seizure control. Radiotherapy and chemotherapy with alkylating agents (procarbazine + CCNU+ vincristine, temozolomide) are effective in reducing the frequency of seizures in patients with pharmacoresistant epilepsy. Newer AEDs (levetiracetam, topiramate, lacosamide) seem to be better tolerated than the old AEDs (phenobarbital, phenytoin, carbamazepine), but there is lack of evidence regarding their superiority in terms of efficacy.

Epilepsy and brain tumors.

Purpose of review To present an overview of the recent findings in pathophysiology and management of epileptic seizures in patients with brain tumors. Recent findings Low-grade gliomas are the most epileptogenic brain tumors. Regarding pathophysiology, the role of peritumoral changes [hypoxia and acidosis, blood–brain barrier (BBB) disruption, increase or decrease of neurotransmitters and receptors] are of increasing importance. Tumor-associated epilepsy and tumor growth could have some common molecular pathways. Total/subtotal surgical resection (with or without epilepsy surgery) allows a seizure control in a high percentage of patients. Radiotherapy and chemotherapy as well have a role. New antiepileptic drugs are promising, both in terms of efficacy and tolerability. The resistance to antiepileptic drugs is still a major problem: new insights into pathogenesis are needed to develop strategies to manipulate the pharmakoresistance. Summary Epileptic seizures in brain tumors have been definitely recognized as one of the major problems in patients with brain tumors, and need specific and multidisciplinary approaches.

Diagnosis and treatment of primary CNS lymphoma in immunocompetent patients: guidelines from the European Association for Neuro-Oncology.

The management of primary CNS lymphoma is one of the most controversial topics in neuro-oncology because of the complexity of the disease and the very few controlled studies available. In 2013, the European Association of Neuro-Oncology created a multidisciplinary task force to establish evidence-based guidelines for immunocompetent adults with primary CNS lymphoma. In this Review, we present these guidelines, which provide consensus considerations and recommendations for diagnosis, assessment, staging, and treatment of primary CNS lymphoma. Specifically, we address aspects of care related to surgery, systemic and intrathecal chemotherapy, intensive chemotherapy with autologous stem-cell transplantation, radiotherapy, intraocular manifestations, and management of elderly patients. The guidelines should aid clinicians in their daily practice and decision making, and serve as a basis for future investigations in neuro-oncology.

Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial

BACKGROUND Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article. METHODS For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 (IELSG32) trial, HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and measurable disease were enrolled from 53 cancer centres in five European countries (Denmark, Germany, Italy, Switzerland, and the UK) and randomly assigned (1:1:1) to receive four courses of methotrexate 3·5 g/m(2) on day 1 plus cytarabine 2 g/m(2) twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m(2) on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m(2) on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after the first stage were then randomly allocated between whole-brain radiotherapy and autologous stem cell transplantation. A permuted blocks randomised design (block size four) was used for both randomisations, and a computer-generated randomisation list was used within each stratum to preserve allocation concealment. Randomisation was stratified by IELSG risk score (low vs intermediate vs high). No masking after assignment to intervention was used. The primary endpoint of the first randomisation was the complete remission rate, analysed by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT01011920. FINDINGS Between Feb 19, 2010, and Aug 27, 2014, 227 eligible patients were recruited. 219 of these 227 enrolled patients were assessable. At median follow-up of 30 months (IQR 22-38), patients treated with rituximab and thiotepa had a complete remission rate of 49% (95% CI 38-60), compared with 23% (14-31) of those treated with methotrexate-cytarabine alone (hazard ratio 0·46, 95% CI 0·28-0·74) and 30% (21-42) of those treated with methotrexate-cytarabine plus rituximab (0·61, 0·40-0·94). Grade 4 haematological toxicity was more frequent in patients treated with methotrexate-cytarabine plus rituximab and thiotepa, but infective complications were similar in the three groups. The most common grade 3-4 adverse events in all three groups were neutropenia, thrombocytopenia, anaemia, and febrile neutropenia or infections. 13 (6%) patients died of toxicity. INTERPRETATION With the limitations of a randomised phase 2 study design, the IELSG32 trial provides a high level of evidence supporting the use of MATRix combination as the new standard chemoimmunotherapy for patients aged up to 70 years with newly diagnosed primary CNS lymphoma and as the control group for future randomised trials. FUNDING Associazione Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Foundation.

Ependymomas in Adults

Ependymomas are rare primary central nervous system tumors in adults. They occur most commonly in the spinal cord, where histopathologic evaluation is critical to differentiate the grade I myxopapillary ependymoma from the grade II ependymoma or grade III anaplastic ependymoma. Brain ependymomas are either grade II or III. Treatment for all grades and types includes maximum surgical resection. For myxopapillary ependymoma, complete removal while maintaining capsule integrity may be curative. Some grade II ependymomas may be observed carefully after imaging confirms complete resection, but grade III tumors require adjuvant radiation treatment. Radiation commonly is given to the region of tumor, except in cases in which there is imaging or cerebrospinal fluid evidence of tumor dissemination. Chemotherapy has not been studied extensively, although most reports suggest only modest benefit. Ongoing laboratory studies have uncovered important signal transduction pathways that may be better therapeutic targets, leading to the development of clinical trials using targeted agents.

Leptomeningeal metastasis: A Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials

PURPOSE To date, response criteria and optimal methods for assessment of outcome have not been standardized in patients with leptomeningeal metastasis (LM). METHODS A Response Assessment in Neuro-Oncology working group of experts in LM critically reviewed published literature regarding randomized clinical trials (RCTs) and trial design in patients with LM. RESULTS A literature review determined that 6 RCTs regarding the treatment of LM have been published, all of which assessed the response to intra-CSF based chemotherapy. Amongst these RCTs, only a single trial attempted to determine whether intra-CSF chemotherapy was of benefit compared with systemic therapy. Otherwise, this pragmatic question has not been formally addressed in patients with solid cancers and LM. The methodology of the 6 RCTs varied widely with respect to pretreatment evaluation, type of treatment, and response to treatment. Additionally there was little uniformity in reporting of treatment-related toxicity. One RCT suggests no advantage of combined versus single-agent intra-CSF chemotherapy in patients with LM. No specific intra-CSF regimen has shown superior efficacy in the treatment of LM, with the exception of liposomal cytarabine in patients with lymphomatous meningitis. Problematic with all RCTs is the lack of standardization with respect to response criteria. There was considerable variation in definitions of response by clinical examination, neuroimaging, and CSF analysis. CONCLUSION Based upon a review of published RCTs in LM, there exists a significant unmet need for guidelines for evaluating patients with LM in clinical practice as well as for response assessment in clinical trials.

Ependymomas of the adult: molecular biology and treatment.

Purpose of reviewTo review state of art and relevant advances in the molecular biology and management of ependymomas of the adult. Recent findingsEpendymomas of the adult are uncommon neoplasms of the central nervous system, and may occur either in the brain or the spinal cord. Compared with intracranial ependymomas, spinal ependymomas are less frequent and exhibit a better prognosis. Studies performed on genetic changes in ependymoma provide some insight into the pathogenesis and prognostic markers and yield new therapeutic targets, particularly focused on signal transduction modulators. The majority of studies have shown a major impact of extent of resection; thus, a complete resection must be performed, whenever possible, at first surgery or at reoperation. Involved field radiotherapy is recommended for anaplastic or incompletely resected grade II tumors. Craniospinal irradiation is reserved for metastatic disease. Chemotherapy is not advocated as primary treatment, and is best utilized as salvage treatment for patients failing surgery and radiotherapy. SummaryOwing to the rarity of the disease, the literature regarding ependymomas in adults is scarce and limited to retrospective series. Thus, the level of evidence regarding therapeutic strategies is low and universally accepted guidelines are lacking. Molecular biology studies suggest some potential new therapeutic targets.

Targeted therapy in brain metastasis.

Purpose of review To review the state of the art and new developments in the field of targeted agents for brain metastases. Recent findings The huge amount of information on new molecular compounds and the advances in understanding the molecular pathways that mediate brain colonization have led to an increase of interest in preclinical and clinical investigations in the field of brain metastases. Targeted therapies can be employed either on established brain metastases or in a prevention setting. Targeting angiogenesis is an attractive approach. Up to date, large clinical trial datasets have shown that antiangiogenic agents do not increase the risk of bleeding into the brain. Bevacizumab (an anti-VEGF agent) is undergoing investigation in clinical trials on brain metastases from non-small cell lung cancer (NSCLC), breast cancer and melanoma. Sunitinib, a multitarget small molecule tyrosine kinase inhibitor (TKI), is a promising agent in brain metastases from renal cell cancer. The EGFR inhibitors gefitinib and erlotinib have a definite activity in brain metastases from NSCLC with activating EGFR mutations. Regarding HER2-positive breast cancer patients with established brain metastases, lapatinib (small molecule TKI) seems particularly active in association with capecitabine. Lapatinib alone is attractive in the prevention setting. Brain metastases from melanoma with BRAF V600E mutations respond to a specific inhibitor, such as vemurafenib. The immunomodulator ipilimumab is also active on brain metastases from melanoma. Summary The use of targeted agents in brain metastases from solid tumors is promising. The setting of prevention will be probably expanded in the next years. Well designed clinical trials with proper endpoints are needed.