Pleomorphic xanthoastrocytoma (PXA) is a World Health Organization Grade 2 glioma that is uncommon (<1 % all adult gliomas) and seen primarily in children and young adults. PXA has been demonstrated ...to manifest the V600E BRAF mutation in nearly 70 % of all tumors, a mutation that constitutively activates the BRAF/MEK signaling pathway. Assess response and toxicity of a BRAF inhibitor, vemurafenib, in recurrent PXA manifesting the V600E mutation. Four adults 2 males; 2 female: median age 45 years (range 34–53) with surgery, radiation and alkylator refractory recurrent PXA demonstrating the BRAF mutation (V600E) were treated with vemurafenib. A cycle of vemurafenib was defined as 4 weeks of continuous therapy. All toxicities seen were grade 2 and included arthralgia, photosensitivity, fatigue and nausea (1 patient each). The median number of cycles of therapy was 5 (range 2–10). Radiographic response was progressive disease in 1, stable disease in 2 and partial response in 1. Median progression free survival was 5 months (range 2–10 months). Median overall survival was 8 months (range 4–14 months). In this small retrospective series of select patients with recurrent PXA manifesting the BRAF V600E activating mutation, vemurafenib appears to have single agent activity with manageable toxicity. Confirmation in a larger series of similar patients is required.
Glioblastoma (GBM) pathologically is defined as an infiltrative glioma and salvage therapy with bevacizumab is believed to increase the incidence of diffuse and distant invasion as assessed ...radiographically. Eighty adult patients with glioblastoma were treated with surgery followed by radiotherapy (RT) and concurrent and adjuvant temozolomide (TMZ). At first recurrence, 80 patients were treated with single agent bevacizumab. At time of progression, 57 patients were treated with bevacizumab and a cytotoxic chemotherapy, cytotoxic chemotherapy alone or on an investigational trial. Magnetic resonance imaging (MRI) were analyzed at four time points in each patient; at presentation, at first, second and third recurrence. Four patterns of radiographic disease were assessed, local (unifocal disease), distant (second lesion noncontiguous with primary lesion), multifocal (>2 lesions including leptomeningeal dissemination) and diffuse. At presentation 87.5% of glioblastoma were local, 6.25% distant, 3.75% multifocal and 2.5% diffuse. At first recurrence following progression on RT/TMZ and before initiation of bevacizumab, 80% were local, 7.5% distant, 6.25% multifocal (including 1 with CSF dissemination) and 6.25% diffuse. At second recurrence following progression on bevacizumab, 71.25% were local, 8.75% distant, 8.75% multifocal (2/7 with CSF dissemination) and 11.25% were diffuse. At third recurrence (57 patients evaluable), 71.25% were local, 7.0% distant, 7.0% multifocal and 14.0% were diffuse. Survival following progression on bevacizumab did not differ by pattern of radiographic recurrence. A majority of adult patients with GBM at diagnosis manifest MRI-defined local disease and maintain this pattern notwithstanding multiple recurrences and treatment with bevacizumab.
Leptomeningeal metastasis Chamberlain, Marc C
Current opinion in oncology,
2010-November, 2010-Nov, 2010-11-00, 20101101, Letnik:
22, Številka:
6
Journal Article
PURPOSE OF REVIEWLeptomeningeal metastasis occurs in approximately 3–5% of all patients with cancer. A contemporary literature review of methods of diagnosis and treatment of leptomeningeal ...metastasis was performed.
RECENT FINDINGSThe single most important aspect to diagnosis of leptomeningeal metastasis is considering and pursuing the diagnosis in a patient with cancer and neurological signs and symptoms. Evaluation of leptomeningeal metastasis includes contrast-enhanced brain and spine magnetic resonance imaging (MRI) and a radionuclide cerebrospinal fluid (CSF) flow study if leptomeningeal metastasis-directed therapy is being considered. Treatment often requires involved-field radiotherapy to bulky or symptomatic disease sites as well as intra-CSF and systemic chemotherapy. The use of high-dose systemic therapy may benefit patients with leptomeningeal metastasis and obviate the need for intra-CSF chemotherapy. Intra-CSF drug therapy primarily utilizes one of three chemotherapeutic agents (i.e. methotrexate, cytosine arabinoside and thio-TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery. Novel and increasingly utilized intra-CSF agents in the treatment of leptomeningeal metastasis are targeted monoclonal antibodies such as rituximab and trastuzumab.
SUMMARYAlthough treatment of leptomeningeal metastasis is palliative with median patient survival of 2–3 months (15% of patients with leptomeningeal metastasis survive 1 year), treatment may afford stabilization and protection from further neurologic deterioration in patients with leptomeningeal metastasis.
Temozolomide-based chemotherapy represents an incremental improvement in the treatment of patients with high-grade gliomas. Notwithstanding a survival benefit in a subset of patients with high-grade ...gliomas, temozolomide (TMZ; Temodar
®
, Schering-Plough Pharmaceuticals, NJ, USA) is the primarily palliative treatment for the vast majority of patients. Indeed, for patients with newly diagnosed glioblastoma, the median increase in survival for treatment with TMZ and radiotherapy is only 2.5 months compared with radiotherapy alone. Additionally, recent studies suggest that 60-75% of patients with glioblastoma derive no benefit from treatment with TMZ. For the treatment of recurrent anaplastic gliomas, more than 50% of patients fail TMZ treatment with cancer progression at 6 months, demonstrating that TMZ is only a modestly effective chemotherapy. In addition, 15-20% of patients treated with TMZ develop clinically significant toxicity, which can leave further treatment unsafe. Despite the availability of TMZ, there is still a substantial need for a chemotherapeutic agent that is more effective and safe. In fact, there still remains a significant unmet need for more effective treatments of high-grade gliomas (improved palliation or cure), whether that treatment be by surgery, radiotherapy, chemotherapy or any yet to be developed type of treatment, such as 'targeted therapies'.
Neoplastic Meningitis Chamberlain, Marc C.
The oncologist (Dayton, Ohio),
September 2008, Letnik:
13, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Learning Objectives
After completing this course, the reader should be able to:
Describe the epidemiology of leptomeningeal metastasis.
Participate in the diagnosis of leptomeningeal metastasis.
...Engage in the treatment of leptomeningeal metastasis.
This article is available for continuing medical education credit at CME.TheOncologist.com
Background.
Neoplastic meningitis (NM) is a common problem in neuro‐oncology, occurring in approximately 5% of all patients with cancer.
Methods.
Notwithstanding frequent focal signs and symptoms, NM is a disease affecting the entire neuraxis, and therefore staging and treatment need encompass all cerebrospinal fluid (CSF) compartments.
Results.
Central nervous system staging of NM includes contrast‐enhanced cranial computerized tomography or magnetic resonance imaging (MR‐Gd), contrast‐enhanced spine magnetic resonance imaging or computerized tomographic myelography and radionuclide CSF flow study. Treatment of NM incorporates involved‐field radiotherapy of bulky or symptomatic disease sites and intra‐CSF drug therapy. The inclusion of concomitant systemic therapy may benefit patients with NM and may obviate the need for intra‐CSF chemotherapy. At present, intra‐CSF drug therapy is confined to three chemotherapeutic agents (i.e., methotrexate, cytosine, arabinoside, and thio‐TEPA) administered by a variety of schedules either by intralumbar or intraventricular drug delivery.
Conclusions.
Although treatment of NM is palliative with an expected median patient survival of 2 to 6 months, it often affords stabilization and protection from further neurologic deterioration in patients with NM.
This review summarizes the epidemiology, diagnosis, and treatment of neoplastic meningitis.
Leptomeningeal metastasis (LM) results from metastatic spread of cancer to the leptomeninges, giving rise to central nervous system dysfunction. Breast cancer, lung cancer, and melanoma are the most ...frequent causes of LM among solid tumors in adults. An early diagnosis of LM, before fixed neurologic deficits are manifest, permits earlier and potentially more effective treatment, thus leading to a better quality of life in patients so affected. Apart from a clinical suspicion of LM, diagnosis is dependent upon demonstration of cancer in cerebrospinal fluid (CSF) or radiographic manifestations as revealed by neuraxis imaging. Potentially of use, though not commonly employed, today are use of biomarkers and protein profiling in the CSF. Symptomatic treatment is directed at pain including headache, nausea, and vomiting, whereas more specific LM-directed therapies include intra-CSF chemotherapy, systemic chemotherapy, and site-specific radiotherapy. A special emphasis in the review discusses novel agents including targeted therapies, that may be promising in the future management of LM. These new therapies include anti-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors erlotinib and gefitinib in nonsmall cell lung cancer, anti-HER2 monoclonal antibody trastuzumab in breast cancer, anti-CTLA4 ipilimumab and anti-BRAF tyrosine kinase inhibitors such as vermurafenib in melanoma, and the antivascular endothelial growth factor monoclonal antibody bevacizumab are currently under investigation in patients with LM. Challenges of managing patients with LM are manifold and include determining the appropriate patients for treatment as well as the optimal route of administration of intra-CSF drug therapy.
Treatment of leptomeningeal metastasis (LMD) remains challenging due to advanced systemic disease at presentation and limited treatment options. All patients underwent standard pre-treatment LMD ...evaluation including CSF assessment (cytology or flow cytometry), brain and spine MR imaging, and radioisotope CSF flow study. DepoCyt (liposomal cytarabine) was administered intraventricularly (
n
= 80) or intralumbar (
n
= 40) at 50 mg every 2 weeks ×4 and then every 4 weeks ×6 in responding patients. Dexamethasone (4 mg orally twice per day ×5 days) was co-administered with each DepoCyt treatment. Patients were seen with each DepoCyt treatment and assessed for toxicity. 120 adult patients median age 51 years (range 33–68) with LMD were treated with DepoCyt. DepoCyt Common Toxicity Criteria ≥Grade 3 neurotoxicity was seen in 60 cycles (11.5 %) in 28 patients (23.3 %). Toxicity included bacterial meningitis (3.75 % of ventricular treatments: 0 % of lumbar treatments); chemical meningitis (17.5:15 %); communicating hydrocephalus (3.75:5 %); conus medullaris/cauda equina syndrome (5:5 %); decreased visual acuity (5:2.5 %); encephalopathy (5:5 %); leukoencephalopathy (7.5:2.5 %); myelopathy (2.5:2.5 %); radiculopathy (1.25:5 %); and seizures (1.25:2.5 %). Distribution of toxicity was similar regardless of route of administration (ventricular vs. lumbar). Toxicities were transient in 34 episodes (57 %) and permanent in 26 (43 %). There were no treatment-related deaths however 20 treatment-related toxicities (32.2 %) required hospitalization. In this retrospective case series, DepoCyt is generally well tolerated however a subset of patients (12.5 %) not easily identified pre-treatment, develop serious treatment-related neurological complications that may be persistent and impact quality of life.
Hydroxyurea (HU), an orally administered chemotherapy, has become the
de facto
standard chemotherapeutic agent in patients with surgically and radiation refractory meningiomas based on a limited ...literature. A retrospective case series of 35 patients with recurrent WHO Grade 2 (
n
= 22) or 3 (
n
= 13) meningioma treated with HU following progression after surgery and radiotherapy was collated with primary study objectives of overall response rate, median and progression free survival (PFS) at 6-months. Thirty-five patients (25 women; 10 men: median age 63 years, range 34–86) with recurrent high-grade meningioma were treated with HU (1,000 mg/m
2
orally divided twice per day; one cycle operationally defined as 4 weeks of daily HU). Patients had progressed radiographically after prior therapy with surgery (35/35) and radiotherapy (35/35: external beam radiotherapy 35/35; stereotactic radiotherapy 35/35). No patient received prior chemotherapy or targeted therapy before instituting HU. Patients received 0.5–7 cycles (median 2.0) of HU with modest toxicity (28.5% all grades and 8.5% grade 3+ anemia or fatigue). There were no radiographic responses, 43% of patients had stable disease and 57% manifested progressive disease at first evaluation. The overall PFS was 3.0% at 6 months (median PFS 2.0 months; 95% CI 1.6–2.4). The majority of patients (80%) following progression on HU were subsequently treated on an investigational trial. In this retrospective series, HU though well tolerated and convenient appeared to have very limited activity, raise questions of what constitutes effective salvage therapy and indicates an unmet need for alternative treatments for recurrent high-grade meningiomas.
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