To provide guidance to clinicians regarding therapy for patients with brain metastases from solid tumors.
ASCO convened an Expert Panel and conducted a systematic review of the literature.
Thirty-two ...randomized trials published in 2008 or later met eligibility criteria and form the primary evidentiary base.
Surgery is a reasonable option for patients with brain metastases. Patients with large tumors with mass effect are more likely to benefit than those with multiple brain metastases and/or uncontrolled systemic disease. Patients with symptomatic brain metastases should receive local therapy regardless of the systemic therapy used. For patients with asymptomatic brain metastases, local therapy should not be deferred unless deferral is specifically recommended in this guideline. The decision to defer local therapy should be based on a multidisciplinary discussion of the potential benefits and harms that the patient may experience. Several regimens were recommended for non-small-cell lung cancer, breast cancer, and melanoma. For patients with asymptomatic brain metastases and no systemic therapy options, stereotactic radiosurgery (SRS) alone should be offered to patients with one to four unresected brain metastases, excluding small-cell lung carcinoma. SRS alone to the surgical cavity should be offered to patients with one to two resected brain metastases. SRS, whole brain radiation therapy, or their combination are reasonable options for other patients. Memantine and hippocampal avoidance should be offered to patients who receive whole brain radiation therapy and have no hippocampal lesions and 4 months or more expected survival. Patients with asymptomatic brain metastases with either Karnofsky Performance Status ≤ 50 or Karnofsky Performance Status < 70 with no systemic therapy options do not derive benefit from radiation therapy.Additional information is available at www.asco.org/neurooncology-guidelines.
Chordomas are rare malignant tumors that originate from the notochord remnants and occur in the skull base, spine and sacrum. Due to a very limited understanding of the molecular pathogenesis of ...chordoma, there are no adjuvant and molecular therapies besides surgical resection and radiation therapy. microRNAs (miRNAs) are small noncoding regulatory RNA molecules with critical roles in cancer. The role of miRNAs in chordomas is mostly unknown. We uncover microRNA-608 (miR-608) and microRNA-34a (miR-34a) as novel tumor suppressive microRNAs that regulate malignancy in chordoma. We find that miR-608 and miR-34a expressions are downregulated in human chordoma cell lines and primary cells at least partially via alteration of their genes' copy numbers. We identify the commonly deregulated oncogenes EGFR and Bcl-xL as direct targets of miR-608 and the receptor tyrosine kinase MET as direct target of miR-34a. We show that EGFR and MET activations promote chordoma cell proliferation and invasion and that pharmacological inhibition of EGFR and MET inhibits chordoma cell proliferation and survival. We demonstrate that restoration of miR-608 and miR-34a inhibits cell proliferation and invasion and induces apoptosis in chordoma cells. We find that miR-34a inversely correlates with MET expression and miR-608 inversely correlates with EGFR expression in chordoma cells. These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Evolving interest in meningioma, the most common primary brain tumor, has refined contemporary management of these tumors. Problematic, however, is the paucity of prospective clinical trials that ...provide an evidence-based algorithm for managing meningioma. This review summarizes the published literature regarding the treatment of newly diagnosed and recurrent meningioma, with an emphasis on outcomes stratified by WHO tumor grade. Specifically, this review focuses on patient outcomes following treatment (either adjuvant or at recurrence) with surgery or radiation therapy inclusive of radiosurgery and fractionated radiation therapy. Phase II trials for patients with meningioma have recently completed accrual within the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer consortia, and Phase III studies are being developed. However, at present, there are no completed prospective, randomized trials assessing the role of either surgery or radiation therapy. Successful completion of future studies will require a multidisciplinary effort, dissemination of the current knowledge base, improved implementation of WHO grading criteria, standardization of response criteria and other outcome end points, and concerted efforts to address weaknesses in present treatment paradigms, particularly for patients with progressive or recurrent low-grade meningioma or with high-grade meningioma. In parallel efforts, Response Assessment in Neuro-Oncology (RANO) subcommittees are developing a paper on systemic therapies for meningioma and a separate article proposing standardized end point and response criteria for meningioma.
This book surveys the life and work of the great American composer Elliott Carter (1908–2012). It examines his formative, and often ambivalent, engagements with Charles Ives and other ...“ultra-modernists”, with the classicist ideas he encountered at Harvard and in his three years of study with Nadia Boulanger in Paris; and with the populism developed by his friends Aaron Copland and Marc Blitzstein in Depression-era New York, and the unique synthesis of modernist idioms that he began to develop in the late 1940s. The book re-groups the central phase of Carter’s career, from the Cello Sonata to Syringa in terms of Carter’s synthesis of European and American modernist idioms, or “neo-modernism,” and his complex relation to the European avant-garde. It devotes particular attention to the large number of instrumental and vocal works of Carter’s last two decades, including his only opera, What Next?, and a final legacy project: seven works for voice and large ensemble to poems by the founding generation of American modern poetry: e.e. cummings, T.S. Eliot, Marianne Moore, Ezra Pound, Wallace Stevens and William Carlos Williams.
Summary CNS metastases are the most common cause of malignant brain tumours in adults. Historically, patients with brain metastases have been excluded from most clinical trials, but their inclusion ...is now becoming more common. The medical literature is difficult to interpret because of substantial variation in the response and progression criteria used across clinical trials. The Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) working group is an international, multidisciplinary effort to develop standard response and progression criteria for use in clinical trials of treatment for brain metastases. Previous efforts have focused on aspects of trial design, such as patient population, variations in existing response and progression criteria, and challenges when incorporating neurological, neuro-cognitive, and quality-of-life endpoints into trials of patients with brain metastases. Here, we present our recommendations for standard response and progression criteria for the assessment of brain metastases in clinical trials. The proposed criteria will hopefully facilitate the development of novel approaches to this difficult problem by providing more uniformity in the assessment of CNS metastases across trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Low-grade infiltrating gliomas in adults include diffuse astrocytoma, oligoastrocytoma and oligodendroglioma. The current gold standard diagnosis of these tumors relies on histological ...classification; however, emerging molecular abnormalities discovered in these tumors are playing an increasingly prominent part in the process of tumor diagnosis and, consequently, patient management. The frequency and clinical importance of tumor protein p53 (TP53) abnormalities, deletions involving chromosomes 1p and 19q, O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status, abnormalities in the PTEN tumor suppressor gene and the BRAF oncogene, and isocitrate dehydrogenase (IDH) mutations have become better defined. Molecular markers have not, historically, had an important role in determining the course of treatment for patients with low-grade gliomas, but ongoing phase III clinical trials incorporate 1p deletion or 1p19q codeletion status-and future trials plan to incorporate MGMT promoter methylation status-as stratification factors. Future trials will need to incorporate IDH mutational status in addition to these factors. Ultimately, molecular marker assessment will, hopefully, improve the accuracy of tumor diagnosis and enhance the effectiveness of treatment to achieve improved patient outcomes.
The discovery in 2008 that many adult gliomas harbor a hitherto unknown mutation in the metabolic gene isocitrate dehydrogenase (IDH) initiated revolutionary advances in our understanding of the ...biology, and correspondingly our classification, of gliomas. IDH mutations are found in most nonglioblastoma adult gliomas and portend a better prognosis. Massive efforts have unraveled many of the pleiotropic cellular effects of these mutations and spawned several lines of investigation to target the effect to therapeutic benefit. In this article are reviewed the implications of the IDH mutation in gliomas, in particular focusing on recent studies that have culminated in a rare positive phase 3 trial in these generally refractory tumors.The discovery in 2008 that many adult gliomas harbor a hitherto unknown mutation in the metabolic gene isocitrate dehydrogenase (IDH) initiated revolutionary advances in our understanding of the biology, and correspondingly our classification, of gliomas. IDH mutations are found in most nonglioblastoma adult gliomas and portend a better prognosis. Massive efforts have unraveled many of the pleiotropic cellular effects of these mutations and spawned several lines of investigation to target the effect to therapeutic benefit. In this article are reviewed the implications of the IDH mutation in gliomas, in particular focusing on recent studies that have culminated in a rare positive phase 3 trial in these generally refractory tumors.
Approximately 2500 persons in the United States receive a diagnosis of isocitrate dehydrogenase (IDH)–mutated grade 2 glioma each year.
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These patients tend to be young (median age, 40 years), and ...most have tumor-related epilepsy and grapple with a tumor that may affect cognition, employment, and other aspects of life. These tumors typically become refractory to treatment and are eventually fatal, belying their designation as “low-grade” gliomas. Both fractionated radiotherapy and alkylator-based chemotherapy help control these tumors but convey a substantial risk of permanent toxic effects. With radiation therapy, such effects include fatigue, alopecia, radiation necrosis, and particularly, cognitive dysfunction; chemotherapy . . .
A multicenter phase II study was conducted to assess the efficacy of rituximab, methotrexate, procarbazine, and vincristine (R-MPV) followed by consolidation reduced-dose whole-brain radiotherapy ...(rdWBRT) and cytarabine in primary CNS lymphoma.
Patients received induction chemotherapy with R-MPV (five to seven cycles); those achieving a complete response (CR) received rdWBRT (23.4 Gy), and otherwise, standard WBRT was offered (45 Gy). Consolidation cytarabine was given after the radiotherapy. The primary end point was 2-year progression-free survival (PFS) in patients receiving rdWBRT. Exploratory end points included prospective neuropsychological evaluation, analysis of magnetic resonance imaging (MRI) white matter changes using the Fazekas scale, and evaluation of the apparent diffusion coefficient (ADC) as a prognostic factor.
Fifty-two patients were enrolled, with median age of 60 years (range, 30 to 79 years) and median Karnofsky performance score of 70 (range, 50 to 100). Thirty-one patients (60%) achieved a CR after R-MPV and received rdWBRT. The 2-year PFS for this group was 77%; median PFS was 7.7 years. Median overall survival (OS) was not reached (median follow-up for survivors, 5.9 years); 3-year OS was 87%. The overall (N = 52) median PFS was 3.3 years, and median OS was 6.6 years. Cognitive assessment showed improvement in executive function (P < .01) and verbal memory (P < .05) after chemotherapy, and follow-up scores remained relatively stable across the various domains (n = 12). All examined MRIs (n = 28) displayed a Fazekas score of ≤ 3, and no patient developed scores of 4 to 5; differences in ADC values did not predict response (P = .15), PFS (P = .27), or OS (P = .33).
R-MPV combined with consolidation rdWBRT and cytarabine is associated with high response rates, long-term disease control, and minimal neurotoxicity.
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