Systemic therapy for recurrent meningioma.

INTRODUCTION: Meningioma comprise 20-30% of all primary brain tumors. Notwithstanding surgery and radiotherapy, a subset of patients will manifest recurrent meningioma. Systemic therapy is recommended only when further surgery and radiotherapy are not possible. No prospective study with a high level of evidence is available to inform as to recommendations regarding systemic therapy. AREAS COVERED: We aim to summarize systemic therapies for recurrent meningioma. Expert commentary: Hydroxurea, temozolomide, irinotecan, the combination of cyclophosphamide/adriamycine/vincristine, interferon-alpha, somatostatin analogs, mifepristone, megestrol acetate, imatinib, erlotinib and gefitinib are considered as having limited efficacy. Potential activity of VEGF (vascular endothelial growth factor) inhibitors such as sunitinib, valatinib, and bevacizumab is suggested in small non-controlled studies and requires validation in randomized trials. The identification of new prognostic markers such as TERT promoter mutations and potential new therapeutic targets, such as KLF4, AKT1, TRAF7, and SMO mutations hopefully facilitate this endeavor.

Treatment of newly diagnosed malignant glioma in the elderly people: new trials that impact therapy.

Glioblastoma (GB), World Health Organization Grade 4 glioma, is the most common malignant primary brain tumour with an annual incidence of 12,943 cases in the United States . It is a tumour of the elderly people with a median age of onset of 64 years, although children and young adults are also affected. GB is associated with a poor prognosis; despite best treatment, most community-based patients will not survive 1 year . Cures are rare and overall survival rates at 2 and 5 years are 26-48% and 12%, respectively, in highly selected, contemporary, clinical trial eligible patients . For protocol eligible US patients, the median survival is 16-17 months, which is partly a reflection of improved supportive care, recognition of pseudoprogression, exclusion of patients undergoing biopsy only and availability of bevacizumab at recurrence . Initial treatment for patients with high performance [Karnofsky Performance Status (KPS) > 60 and age < 71 years) consists of maximal safe surgical resection followed by adjuvant focal, external beam radiotherapy (RT) with concurrent temozolomide (TMZ) chemotherapy and post-RT TMZ for 6 months . TMZ and carmustine (BCNU) biodegradable wafer (Gliadel) are the only adjuvant chemotherapies that have improved survival in randomised GB clinical trials . The current standard treatment is based upon a European Organization for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada (NCIC) randomised, phase 3 trial of 573 patients with newly diagnosed GB (age 19-71 years and World Health Organization Performance Status ≤ 2) that compared RT alone [total dose 60 Gray (Gy)] to TMZ chemotherapy in combination with RT (total 60 Gy), followed by 6 months of post-RT TMZ (4,6,8).

A retrospective case series of 103 consecutive patients with leptomeningeal metastasis and breast cancer.

Approximately 2-5 % of patients with breast cancer (BC) develop leptomeningeal metastasis (LM). 103 consecutive patients with BC were diagnosed with LM and initially treated with intra-CSF liposomal cytarabine from 2007 to 2011 at a single institution. Correlations were determined with respect to patient characteristics and BC subtype with regard to overall survival (OS). At LM diagnosis, 61 % of patients had a 0-2 performance status (PS), the remaining 39 % were severely neurologically impaired. Regardless of PS, all patients received intra-cerebrospinal fluid (CSF) liposomal cytarabine as first-line treatment. Systemic treatment and radiotherapy were also given in 58 and 17 % of patients respectively as clinically appropriate. Second- (intra-CSF thiotepa) and third-line (intra-CSF methotrexate) treatment was administered in 24 and 6 patients respectively. Median OS was 3.8 months (range 1 day-2.8 years). In multivariate analysis, an initial combined treatment, a second-line treatment with intra-CSF thiotepa, an initial clinical response, and a non-'ER/PR/HER2 negative' BC were significantly associated with a better OS. Median OS in this heterogeneous retrospective case series was similar to that of previously observed BC patients treated with intra-CSF methotrexate suggesting intra-CSF liposomal cytarabine is a reasonable first choice therapy of BC-related LM.

Primary intraocular lymphoma: an International Primary Central Nervous System Lymphoma Collaborative Group Report.

BACKGROUND: Primary intraocular lymphoma (PIOL) is an uncommon subset of primary central nervous system lymphoma. Because it is rare and difficult to diagnose, the natural history and optimal management are unknown. PATIENTS AND METHODS: A retrospective study of 83 HIV negative, immunocompetent PIOL patients was assembled from 16 centers in seven countries. RESULTS: Median age at diagnosis was 65. Median ECOG performance status was 0. Presenting symptoms included blurred vision, decreased visual acuity, and floaters. Median time to diagnosis was 6 months. Diagnosis was made by vitrectomy (74), choroidal/retinal biopsy (6) and ophthalmic exam (3). Eleven percent had positive CSF cytology. Initial treatment was categorized as focal in 23 (intra-ocular methotrexate, ocular radiotherapy) or extensive in 53 (systemic chemotherapy, whole brain radiotherapy). Six received none; details are unknown in one. Forty-seven relapsed: brain 47%, eyes 30%, brain and eyes 15%, and systemic 8%. Median time to relapse was 19 months. Focal therapy alone did not increase risk of brain relapse. Median progression free (PFS) and overall survival (OS) were 29.6 and 58 months, respectively, and unaffected by treatment type. CONCLUSION: Treatment type did not affect relapse pattern, median PFS or OS. Focal therapy may minimize treatment toxicity without compromising disease control.

Adult medulloblastoma: multiagent chemotherapy.

In this study, the records of 17 adult patients with medulloblastoma treated with craniospinal radiation and 1 of 2 multiagent chemotherapy protocols were reviewed for progression-free survival, overall survival, and toxicity, and the patients were compared with each other and with similarly treated children and adults. Records of patients treated at 3 institutions were reviewed. Seventeen medulloblastoma patients (11 female, 6 male) with a median age of 23 years (range, 18-47 years) were treated with surgery, craniospinal radiation (CSRT) plus local boost, and 1 of 2 adjuvant chemotherapy regimens. All tumors were infratentorial (10 in 4th ventricle and 7 in left or right hemisphere). Ten patients presented with hydrocephalus, and 7 of them were shunted. Eight patients had gross total resection, 7 had subtotal resection (>50% removed), and 2 had partial resection (<50% removed). Postoperatively, 3 patients had positive cytology and 3 had positive spinal MRI. Five patients were classified as good risk and 12 were classified as poor risk (Chang staging system). Ten patients were treated with the "Packer protocol," consisting of CSRT plus weekly vincristine followed by 8 cycles of cisplatin, lomustine, and vincristine. Seven patients were treated with the Pediatric Oncology Group (POG) protocol, consisting of alternating courses of cisplatin/etoposide and cyclophosphamide/vincristine, followed by CSRT. Eight of 17 patients relapsed, with all 8 relapsing at the primary site. Other relapse sites included the leptomeninges (5), bone (1), and brain (1). The estimated median relapse-free survival (Kaplan-Meier) for all patients was 48 months (95% confidence interval, >26 months to infinity). Median relapse-free survival for patients on the Packer protocol was 26 months, and for those on the POG regimen was 48 months (P = 0.410). Five of 10 on the Packer protocol were relapse-free, while 4 of 7 were relapse-free on the POG regimen. Two patients relapsed during chemotherapy and 6 relapsed after completing all therapy at 18, 18, 26, 30, 40, and 48 months. The estimated median survival of all patients was 56 months (95% confidence interval, 27 to infinity) with 11 patients alive; for the Packer protocol, median survival was 36 months, and for the POG protocol, it was 57 months (P = 0.058). The hazard ratio was 0 (95% confidence interval, 0 to infinity). Toxicity during the Packer protocol was moderately severe, with only 1 of 10 patients able to complete all therapy. Two patients had severe abdominal pain during CSRT + vincristine, and 5 had peripheral neuropathy during vincristine therapy. Hearing loss (>20 dB) occurred in 7, neutropenia (<500 microl) in 6, thrombocytopenia (<50,000 microl) in 6, nephrotoxicity (>25% decrease by creatinine clearance) in 2, and decreased pulmonary function (diffusing capacity for carbon monoxide decrease >40%) in 1. On the POG protocol, only 1 patient had persistent nausea and vomiting, 2 had peripheral neuropathy, and 3 had hearing deficit (>20 dB) or tinnitus. The POG and Packer protocols did not have a statistically significant difference in relapse-free or overall survival because of the small sample size. The POG protocol seemed to have less nonhematologic toxicity. Adults on the Packer protocol appeared to have shorter median survival and greater toxicity than did children. To know whether adding adjuvant chemotherapy to craniospinal radiation in adult therapy increases relapse-free and overall survival, we must await the results of a larger randomized controlled clinical trial.

A comparison between ventricular and lumbar cerebrospinal fluid cytology in adult patients with leptomeningeal metastases.

Leptomeningeal metastases (LMs) are common metastatic complications, occurring in at least 5% of patients with disseminated cancer. Cerebrospinal fluid (CSF) cytology remains the standard for diagnosis and assessment of treatment response, but may be inadequate. Our objective was to compare ventricular and lumbar CSF cytology in patients who had cytologically proven LM and were receiving intra-CSF chemotherapy. Sixty patients with LM, positive lumbar CSF cytology documented at diagnosis, limited extent of CNS disease, and no evidence of CSF flow obstruction were treated with a variety of intra-CSF chemotherapies. All patients underwent a single simultaneous ventricular and lumbar CSF sampling (mean volume of CSF per site examined, 10 ml) to assess response to therapy at either 1 or 2 months after treatment initiation. Ventricular CSF cytology was positive in 44 patients (73%), 35 of whom were also positive by lumbar CSF cytology. Lumbar CSF cytology was positive in 45 patients (75%), of which 35 were also positive by ventricular CSF cytology. Samples were negative at both ventricular and lumbar sites in 6 patients (10%). Paired CSF cytologies were discordant in 19 (32%) patients. The lumbar cytology was negative in 9, whereas the ventricular cytology was positive (lumbar false-negative rate of 17%); the ventricular cytology was negative in 10, whereas the lumbar cytology was positive (ventricular false-negative rate of 20%). In the presence of spinal signs or symptoms of LM, the lumbar CSF cytology was more likely to be positive than was the ventricular (odds ratio = 2.86; 95% confidence interval, 0.86-9.56). Conversely, in the presence of cranial signs or symptoms, the ventricular CSF cytology was more likely to be positive than was the lumbar (odds ratio = 2.71; 95% confidence interval, 0.76-9.71). In this cohort of patients, whose LM was documented initially by positive lumbar CSF cytology, ventricular and lumbar CSF samples obtained during treatment had similar false-negative rates, depending on the site of clinical or radiologic disease. This suggests that both lumbar and ventricular sites must be sampled when assessing treatment response. If clinical or radiographic disease is present only at 1 site, then CSF from that site is more likely to be positive than is CSF obtained from the more distant site.

Recurrent intracranial ependymoma in children: salvage therapy with oral etoposide.

Chronic oral VP-16 (etoposide) is a chemotherapy regimen with a wide application in oncology and documented efficacy against germ cell tumors, lymphomas, Kaposi's sarcoma, and primary brain tumors. This study was performed to assess the toxicity and activity of chronic oral etoposide in the management of children with recurrent intracranial nondisseminated ependymoma. Twelve children (median age of 8 years) with recurrent ependymoma who were refractory to surgery, radiotherapy, and chemotherapy (carboplatinum or the combination of procarbazine, lomustine, and vincristine) were treated with chronic oral etoposide (50 mg/m(2)/day). Treatment-related complications included the following: alopecia (10 children), diarrhea (6), weight loss (5), anemia (4), neutropenia (3), and thrombocytopenia (3). Three children required transfusion (two with packed red blood cells; two with platelets), and two children developed neutropenic fever. No treatment-related deaths occurred. Six children (50%) demonstrated either a radiographic response (two children, both with partial response) or stable disease (four children) with a median duration of response or stable disease of 7 months. In this small cohort of children with recurrent intracranial ependymoma, oral etoposide was well tolerated, produced modest toxicity, and had apparent activity.

Intrathecal treatment of neoplastic meningitis due to breast cancer with a slow-release formulation of cytarabine.

DepoCyte is a slow-release formulation of cytarabine designed for intrathecal administration. The goal of this multi-centre cohort study was to determine the safety and efficacy of DepoCyte for the intrathecal treatment of neoplastic meningitis due to breast cancer. DepoCyte 50 mg was injected once every 2 weeks for one month of induction therapy; responding patients were treated with an additional 3 months of consolidation therapy. All patients had metastatic breast cancer and a positive CSF cytology or neurologic findings characteristic of neoplastic meningitis. The median number of DepoCyte doses was 3, and 85% of patients completed the planned 1 month induction. Median follow up is currently 19 months. The primary endpoint was response, defined as conversion of the CSF cytology from positive to negative at all sites known to be positive, and the absence of neurologic progression at the time the cytologic conversion was documented. The response rate among the 43 evaluable patients was 28% (CI 95%: 14-41%); the intent-to-treat response rate was 21% (CI 95%: 12-34%). Median time to neurologic progression was 49 days (range 1-515(+)); median survival was 88 days (range 1-515(+)), and 1 year survival is projected to be 19%. The major adverse events were headache and arachnoiditis. When drug-related, these were largely of low grade, transient and reversible. Headache occurred on 11% of cycles; 90% were grade 1 or 2. Arachnoiditis occurred on 19% of cycles; 88% were grade 1 or 2. DepoCyte demonstrated activity in neoplastic meningitis due to breast cancer that is comparable to results reported with conventional intrathecal agents. However, this activity was achieved with one fourth as many intrathecal injections as typically required in conventional therapy. The every 2 week dose schedule is a major advantage for both patients and physicians.

Neoplastic meningitis: a guide to diagnosis and treatment.

Neoplastic meningitis is a disease of the entire neuraxis and is pleomorphic in its clinical presentation. Diagnosis is achieved by recognition of the clinical manifestations of neoplastic meningitis followed by neuroradiography of the brain and spinal cord and examination of the cerebrospinal fluid. Treatment, if clinically warranted, includes irradiation of symptomatic or bulky disease and intracerebrospinal fluid chemotherapy following an assessment of the extent of metastatic disease treatment is based on the results of four randomized intracerebrospinal fluid chemotherapy trials.

A randomized controlled trial comparing intrathecal sustained-release cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors.

Standard treatment for neoplastic meningitis requires frequent intrathecal (IT) injections of chemotherapy and is only modestly effective. DepoCyt is a sustained-release formulation of cytarabine that maintains cytotoxic concentrations of the drug in the cerebrospinal fluid (CSF) for more than 14 days after a single 50-mg injection. We conducted a randomized, controlled trial of DepoCyt versus methotrexate in patients with solid tumor neoplastic meningitis. Sixty-one patients with histologically proven cancer and positive CSF cytologies were randomized to receive IT DepoCyt (31 patients) or IT methotrexate (30 patients). Patients received up to six 50-mg doses of DepoCyt or up to sixteen 10-mg doses of methotrexate over 3 months. Treatment arms were well balanced with respect to demographic and disease-related characteristics. Responses occurred in 26% of DepoCyt-treated and 20% of methotrexate-treated patients (P = 0.76). Median survival was 105 days in the DepoCyt arm and 78 days in the methotrexate arm (log-rank P = 0.15). The DepoCyt group experienced a greater median time to neurological progression (58 versus 30 days; log-rank P = 0.007) and longer neoplastic meningitis-specific survival (log-rank P = 0.074; median meningitis-specific survival, 343 versus 98 days). Factors predictive of longer progression-free survival included absence of visible central nervous system disease on neuroimaging studies (P<0.001), longer pretreatment duration of CSF disease (P<0.001), history of intraparenchymal tumor (P<0.001), and treatment with DepoCyt (P = 0.002). The frequency and grade of adverse events were comparable between treatment arms. In patients with solid tumor neoplastic meningitis, DepoCyt produced a response rate comparable to that of methotrexate and significantly increased the time to neurological progression while offering the benefit of a less demanding dose schedule.

AIDS-related central nervous system lymphomas.

PURPOSE: To evaluate combined radio-chemotherapy in patients with AIDS-related lymphomatous meningitis (LM) or primary central nervous system lymphoma (PCNSL). PATIENTS AND METHODS: Eighteen men and 2 women with AIDS had cytologically documented LM. Fifteen patients had systemic non-Hodgkin's lymphoma with LM and 5 patients had PCNSL with CSF dissemination. Standardized pre-treatment evaluations included contrast cranial MRI, placement of an intraventricular reservoir, contrast spine MRI, ophthalmologic evaluation and 111Indium-DTPA CSF flow studies. Regions of bulky or symptomatic disease were treated with limited-field irradiation. Concurrent systemic chemotherapy was administered in 18 patients. All patients were scheduled to receive intraventricular methotrexate (MTX) according to a concentration x time (C x T) drug schedule. In cytologic or clinical failures, patients were treated with salvage therapy using intraventricular ara-C and in a similar manner, patients were treated with intraventricular thio-TEPA following cytologic relapse or clinical failure intraventricular following intraventricular ara-C. Sixty-seven patients (63 men; 4 women) with PCNSL underwent a standardized pre-treatment evaluation as in patients with LM and were treated according to 3 schedules. In the first group (n = 15), comfort care was offered. In the second group (n = 45), whole brain radiotherapy was administered. In the third group (n = 7), patients were treated with combined radio- and chemotherapy using systemic procarbazine, CCNU and vincristine (PCV-3). The third group was selected based on a Karnofsky performance status > or =60, no evidence of disseminated PCNSL, a CD4 count >200, no concurrent opportunistic infection and a patient's desire for aggressive therapy. RESULTS: In the LM patient group, 16 patients were evaluable as 4 patients subsequently withdrew consent for treatment. Median time to tumor progression/survival were as follows: not-treated (n = 4) 12 days/ month; treated non-responding (n = 6) 30 days/2 months; and treated responding (n = 10) 130 days/6 months. In the PCNSL patient group, median range survival were as follows: comfort care (n = 15) 1.5/0.5-3 months; whole brain radiotherapy (n = 45) 4/1.5-5 months; and combined radio-chemotherapy (n = 7) 13/10-18 months. CONCLUSIONS: Combined radio- and chemotherapy is appropriate for a small subset of patients with AIDS and either LM or PCNSL. This approach results in meaningful palliation not strikingly dissimilar from that seen in non-AIDS patients.

Salvage chemotherapy with taxol for recurrent anaplastic astrocytomas.

BACKGROUND: A prospective Phase II study of Taxol in young adult patients with recurrent anaplastic astrocytomas. METHODS: Twenty-four patients (15 men; 9 women) ages 19-45 years (median 31.5), with recurrent anaplastic astrocytomas were treated. All patients had previously been treated with surgery and involved-field radiotherapy (median dose 60 Gy; range 51-61 Gy). Additionally, 22 patients were treated adjuvantly with nitrosourea-based chemotherapy (PCV in 17; BCNU in 5). Fourteen patients were treated with salvage chemotherapy at first recurrence with 1-2 chemotherapy regimens (median 1). Taxol was administered at a fixed dose of 175 mg/m2 given as a 3 h intravenous infusion monthly. Neurological and neuroradiographic evaluation were performed every 8 weeks after 2 courses of Taxol, operationally defined as a single cycle of Taxol. RESULTS: All patients were evaluable. A median of 3.5 cycles of Taxol (range 1-13) were administered. Taxol-related toxicity included: partial alopecia (13 patients); non-disabling peripheral neuropathy (4); neutropenia (4); anemia (3); and thrombocytopenia (2). Four patients required transfusions (2 packed red blood cell; 2 platelet) and one patient was treated for culture negative neutropenic fever. No treatment-related deaths were observed. Three patients (13%) demonstrated a neuroradiographic partial response, 16 patients (67%) demonstrated stable disease and 5 patients (21%) had progressive disease following a single cycle of Taxol. Time to tumor progression ranged from 2-26 months (median 7.5 months). Nineteen patients were offered alternative chemotherapy after failing Taxol of whom 13 clinically responded. Survival ranged from 3-56 months (median 18.5 months). Four patients are alive, all are on alternative chemotherapy regimens. CONCLUSIONS: Taxol demonstrated modest efficacy with manageable toxicity in this heavily pre-treated cohort of young adult patients with recurrent anaplastic astrocytomas.

Salvage chemotherapy with tamoxifen for recurrent anaplastic astrocytomas.

BACKGROUND: A prospective phase 2 study of daily oral tamoxifen citrate in young adults with recurrent anaplastic astrocytomas. METHODS: Twenty-four patients (15 men; 9 women) aged 19 to 45 years (median age, 31.5 years) with recurrent anaplastic astrocytomas were treated. All patients had been treated previously with surgery and involved-field radiotherapy (median dose, 60 Gy; range, 59-61 Gy). In addition, 22 patients were treated adjuvantly with nitrosourea-based chemotherapy (combined procarbazine hydrochloride, lomustine, and vincristine sulfate in 16; carmustine in 6). All patients were treated with salvage chemotherapy at first recurrence, with 1 to 4 chemotherapy regimens (median, 1 regimen). Tamoxifen citrate was administered orally at a fixed dosage of 80 mg/m2 as a single or a twice-daily dosage. Neurologic and neuroradiographic evaluation were performed every 12 weeks, operationally defined as a single cycle of tamoxifen. RESULTS: All patients were able to undergo evaluation. A median of 4 cycles of tamoxifen (range, 1-8 cycles) were administered. No tamoxifen-related toxic effects were seen, nor were there any treatment-related deaths. Four patients (17%) demonstrated a neuroradiographic partial response; 11 patients (46%), stable disease; and 9 patients (38%), progressive disease following a single cycle of tamoxifen. Time to tumor progression ranged from 3 to 25 months (median, 12 months). Survival ranged from 3 to 27 months (median, 13 months). Five patients are alive, with 3 receiving alternative chemotherapy regimens and 2 continuing to receive tamoxifen. In the group with responding and stable disease, median survival was 15 months (range, 8-27 months). CONCLUSION: Tamoxifen demonstrated modest efficacy with no apparent toxic effects in this heavily pretreated cohort of young adults with recurrent anaplastic astrocytomas.

The role of paclitaxel in the treatment of primary and metastatic brain tumors.

The rationale for the use of paclitaxel to treat brain tumors includes impressive activity in a wide array of chemotherapy-resistant solid tumors, in vitro and in vivo evidence of cytotoxicity against primary brain tumors, and a paucity of effective alternative agents. A review of published studies evaluating paclitaxel alone or in combination with other chemotherapeutic agents suggests that paclitaxel alone is not highly active against newly diagnosed or recurrent glioblastoma multiforme. However, additional prospective trials are warranted to evaluate the efficacy of paclitaxel plus conventional cranial irradiation or stereotactic radiosurgery. Single-agent paclitaxel appears to be active against gliomas with an oligodendroglial component and may prove useful both as a component of initial therapy and for recurrent disease. Activity against anaplastic gliomas and brain metastases also should be explored. With radiation, a weekly paclitaxel administration schedule is particularly appealing from pharmacologic, safety, and dose-intensity perspectives. In addition, the dose of paclitaxel must be increased in patients who are concurrently receiving medications that induce the P-450 drug metabolizing system. Primary and metastatic brain tumors constitute a very difficult problem in oncology. Future investigations should be directed at evaluating paclitaxel-based chemotherapy regimens in selected brain tumor types, combining paclitaxel with stereotactic radiosurgery, and determining the importance of other proposed mechanisms of action of paclitaxel (eg, inhibition of angiogenesis and tumor invasion).

Epidural spinal cord compression: a single institution's retrospective experience.

Epidural spinal cord compression (ESCC) is a common metastatic complication occurring in 5% of patients with cancer. We sought to determine retrospectively the frequency of multiple sites of ESCC at presentation and the risk of recurrence of ESCC. Of the cancer patients seen by the University of California San Diego's Neuro-Oncology Service between August 1986 and January 1997, 108 developed ESCC that was documented both clinically and by MRI of the spine. In 77 patients (71%), a single site of ESCC was seen; 31 patients (29%) had multiple sites of ESCC. All sites of ESCC were irradiated. In 7% of patients with single-site ESCC and in 9% of patients with multiple-site ESCC, the disease recurred. Length of survival was similar for patients with single- or multiple-site ESCC (median, 4.5 months) versus patients with recurrent ESCC (median, 7 months). An MRI of the entire spine in patients with suspected ESCC demonstrated multiple sites of ESCC in nearly one-third of patients. In 8% of patients with ESCC, symptomatic ESCC recurred.