Platinum-based chemotherapy in recurrent high-grade glioma patients: retrospective study.

INTRODUCTION: To investigate the efficacy of platinum-based chemotherapy in patients with recurrent high-grade glioma (HGG) who had received previous alkylating line of chemotherapy. MATERIAL AND METHODS: Case notes of patients who had received chemotherapy with carboplatin or cysplatin for recurrent HGG between June 2006 and July 2012 were reviewed. Baseline characteristics and outcomes after treatment were recorded. RESULTS: Forty-eight patients received carboplatin/cysplatin as second line chemotherapy for recurrent HGG (grade III n = 6; grade IV n = 42). The median number of cycles completed was 4. Fifteen patients (28%) had at least minor response, 22 (49%) had stable disease and 11 (23%) had progressive disease. Six month progression-free survival was 30% (52% in patients with grade III glioma and 18% in patients with grade IV glioma). The median time to disease progression from the first treatment with platinum drug was 3.2 months. The median survival was 8 months (10 months for patients with grade III glioma and 7 months for patients with grade IV glioma). Among patients with either stable disease or a partial response, the median survival was 12 months compared with 3 months in patients with progressive disease. No survival or response rate differences were noted regarding the type of previous chemotherapy, nitrosoureas or temozolomide. CONCLUSIONS: Single-agent carboplatin/cysplatin has modest activity in patients with recurrent HGG previously treated with one line of chemotherapy, nitrosoureas or temozolomide. Despite the improvement of median survival of patients achieving stable disease or a partial response to treatment, more effective regimens are required for this patient population.

Prophylactic intrathecal chemotherapy in primary CNS lymphoma.

The role of prophylactic intrathecal chemotherapy in the treatment of primary central nervous system lymphoma remains controversial. We report a retrospective single center study of a cohort of 69 patients with primary central nervous system lymphoma who had been treated with a regimen that combined high intravenous doses of Methotrexate, CCNU, procarbazine and methylprednisolone. Before 2000, patients systematically received intrathecal prophylaxis including Methotrexate, cytarabine, and hydrocortisone delivered either by intraventricular or lumbar injection along with the systemic chemotherapy (group A, n = 39). After this date, the procedure was changed and intrathecal chemotherapy was withdrawn from the protocol (group B, n = 30). The median age and Karnofsky index were comparable in both groups. At the time of analysis, we found no significant difference between patients with and without intrathecal prophylaxis in terms of objective response rate, patterns of relapse, progression-free survival or overall survival. In our study, intrathecal prophylaxis withdrawal from a high dose intravenous Methotrexate-based chemotherapy regimen did not influence disease control and outcome of primary central nervous system lymphoma. Further studies prospectively investigating the role of intrathecal chemoprophylaxis are warranted for this disease.

Up-front temozolomide in elderly patients with anaplastic oligodendroglioma and oligoastrocytoma.

Optimal treatment of anaplastic oligodendroglial tumors (AOT) in elderly patients is debatable. We report a retrospective study of 44 consecutive patients aged 70 years or older [median age: 74 years; median Karnofsky performance status (KPS): 70] treated with up-front chemotherapy using temozolomide (TMZ) at conventional doses until tumor progression. O(6)-methylguanine-DNA methyltransferase promoter (MGMTP) methylation was assessed in 38 patients. Of the 41 evaluable patients, partial response (PR) was seen in 13 (32%) patients, 17 (41%) patients achieved stable disease, while the disease progressed in 11 (27%) patients. Median progression-free survival (PFS) and overall survival (OS) were 6.9 and 12.4 months, respectively. Hematotoxicity grades 3-4 occurred in nine patients (20%). MGMTP was methylated in 50% of patients and was associated with both longer PFS (8.7 versus 5.7 months, P = 0.01) and longer OS (16.1 versus 12.4 months, P = 0.05). The rate of responders to chemotherapy was similar in MGMTP-methylated (38%) and in MGMTP-unmethylated patients (31%), but duration of response was significantly longer in responders with methylated MGMTP than in responders with unmethylated MGMTP (16.1 versus 9.6 months, P = 0.0004). This study demonstrates that a substantial number of elderly patients with AOT can achieve prolonged survival with up-front chemotherapy using TMZ. Further investigation is needed to determine whether this treatment is preferable to initial radiation therapy.

Prognostic stratification of gliomatosis cerebri by IDH1 R132H and INA expression.

Gliomatosis cerebri (GC) constitutes a heterogeneous group of conditions involving diffuse neoplastic glial cell infiltration of the brain. Management is difficult and an obvious challenge is to identify prognostic factors. Alpha-internexin (INA) expression, which is closely related to the 1p19q codeletion, is a strong prognostic marker in oligodendroglial tumors. Similarly, the R132H isocitrate dehydrogenase 1 IDH1 mutation, which can now be detected by use of a specific antibody, predicts better outcome in gliomas. In a retrospective series of 40 GC treated with up-front chemotherapy, we analyzed IDH1(R132H) mutant protein and INA immunohistochemical expression and correlated it with outcome; 17/40 GC expressed IDH1(R132H) and 10/40 GC expressed INA. IDH1(R132H) staining was strongly related to progression-free survival (42.3 vs. 15.5 months for positive IDH1(R132H) vs. negative tumors; P < 0.0001) and overall survival (73.9 vs. 23.6 months; P < 0.0001). This effect was independent of grade, histologic subtype, and INA expression (P < 0.001). Combined expression of IDH1(R132H) and INA was strongly associated with response to chemotherapy (100% vs. 36%; P = 0.003). These data strongly suggest that INA and IDH1(R132H) mutant protein immunohistochemical analysis is of a great prognostic value in biopsied GC.

Nitrosourea-based chemotherapy for low grade gliomas failing initial treatment with temozolomide.

There is a growing evidence of using Temozolomide as upfront therapy for progressive low grade gliomas. No data exist on the efficacy of nitrosoureas as an alternative to radiotherapy in those patients who progress after Temozolomide. We retrospectively reviewed 30 patients with median age of 46 years. Twenty-one patients had pure oligodendrogliomas. Thirteen patients had a non-enhancing tumor at progression after Temozolomide. The chromosomes 1p/19q were co-deleted in 5 cases and retained in 10 cases. Response rate was 10% (3 minor responses achieved in non-enhancing tumors). Tolerance was acceptable (17% grade III and IV myelosupression). Median PFS was 6.5 months. Median OS from start of salvage treatment was 23.4 months. Tumors without contrast enhancement demonstrated a better prognosis than those with contrast enhancement both in term of PFS (P = 0.0003) and OS (P = 0.0006). Chromosomes 1p/19q codeletion was not predictive for objective response to salvage treatment but correlated with a better PFS (P = 0.02). In conclusion, salvage NU chemotherapy provide disappointing results in TMZ-pretreated low grade gliomas (LGG), which should be treated in priority by conventional radiotherapy especially in LGG that display contrast enhancement at progression.

Up-front temozolomide in elderly patients with glioblastoma.

Upfront temozolomide (TMZ) is often proposed for elderly patients with malignant gliomas as an alternative to radiotherapy (RT). A recent randomized trial showed that RT provides a survival benefit in elderly glioblastoma patients (>or=70 years) with good performance status (KPS >or= 70) compared with supportive care alone (median survival (MS) = 29.1 vs. 16.9 weeks). We retrospectively analyzed all patients who were eligible for this trial, but who refused to participate and were finally treated with TMZ alone. Thirty-nine eligible patients (median age: 75 years (range 70-83), median KPS: 70 (range 70-80), histologically proven glioblastomas) were treated up-front with oral TMZ for 1-12 cycles (mean = 5). One complete response and 10 partial responses were observed. Overall median survival (MS) was 36 weeks and median progression-free survival (PFS) was 20 weeks for the whole group. MS was 27.4 weeks and PFS was 19.5 weeks for the 27 patients that did not receive second-line treatment at progression. Eight grade III/IV toxicities (seven hematologic, one gastro-intestinal) were seen, but no treatment-related deaths were observed. These preliminary results support further randomized studies comparing TMZ with RT.

No association of (-131C-->G) variant of CHI3L1 gene with risk of glioblastoma and prognosis.

Expression of CHI3L1 (YKL-40) has been correlated with prognosis of glioblastoma. The variant allele (-131C-->G) of CHI3L1 promoter results in a lower transcription of CHI3L1. Therefore, we tested the hypothesis that the G variant could protect against the risk of gliomas or have a favorable prognostic impact. DNA from 296 glioblastoma patients and 190 controls were genotyped on the -131 allele. Tumor RNA was obtained from 108 patients for CHI3L1 transcript quantification. Neither genotype nor allele distribution differed between patients and controls. There was no significant difference in survival between the CC, CG, and GG patients despite the few GG patients tended to have a longer survival. There was no correlation between genotype and CHI3L1 expression in tumor samples. Taken together our data suggest that the variant allele (-131C-->G) of CHI3L1 promoter has no significant impact on survival and is not a prognostic factor for glioblastoma.

The 61 A/G EGF polymorphism is functional but is neither a prognostic marker nor a risk factor for glioblastoma.

The A/G61 polymorphism located in the 5'UTR of the EGF gene has been found to be both a risk factor and a prognostic factor in glioblastoma (GBM), but the functional consequences have not been investigated. Here we show, in vitro, that this polymorphism is functional, in that the G allele promoter is 40% more active than the A variant (P < 0.001). However, analysis of a large series of 209 GBM patients and 214 control subjects did not confirm that A/G61 polymorphism is a significant risk factor for GBM, despite a trend for higher GG frequency in these patients. Furthermore, A/G61 polymorphism was not a prognostic factor for survival in GBM patients, although it does appear to affect progression-free survival.

Analysis of temozolomide resistance in low-grade gliomas using a mechanistic mathematical model.

Understanding how tumors develop resistance to chemotherapy is a major issue in oncology. When treated with temozolomide (TMZ), an oral alkylating chemotherapy drug, most low-grade gliomas (LGG) show an initial volume decrease but this effect is rarely long lasting. In addition, it has been suggested that TMZ may drive tumor progression in a subset of patients as a result of acquired resistance. Using longitudinal tumor size measurements from 121 patients, the aim of this study was to develop a semi-mechanistic mathematical model to determine whether resistance of LGG to TMZ was more likely to result from primary and/or from chemotherapy-induced acquired resistance that may contribute to tumor progression. We applied the model to a series of patients treated upfront with TMZ (n = 109) or PCV (procarbazine, CCNU, vincristine) chemotherapy (n = 12) and used a population mixture approach to classify patients according to the mechanism of resistance most likely to explain individual tumor growth dynamics. Our modeling results predicted acquired resistance in 51% of LGG treated with TMZ. In agreement with the different biological effects of nitrosoureas, none of the patients treated with PCV were classified in the acquired resistance group. Consistent with the mutational analysis of recurrent LGG, analysis of growth dynamics using mathematical modeling suggested that in a subset of patients, TMZ might paradoxically contribute to tumor progression as a result of chemotherapy-induced resistance. Identification of patients at risk of developing acquired resistance is warranted to better define the role of TMZ in LGG.

Population pharmacokinetic study of methotrexate in patients with lymphoid malignancy.

PURPOSE: A population pharmacokinetic model was developed to describe dose-exposure relationships of methotrexate (MTX) in adults with lymphoid malignancy; this is in order to explore the interindividual variability in relationship with the different physiopathological variables. The final model was applied to the Bayesian estimation of MTX concentrations using two blood samples. METHODS: Fifty-one patients receiving 136 courses of MTX (1-6 per patient) were included in this study. The data was analysed using NONMEM software. A linear two-compartment model with linear elimination best described the data. Setting mean parameters values and variabilities to population values, we obtained Bayesian prediction of MTX pharmacokinetic parameters and concentrations. The predictive performance was evaluated by comparing the Bayesian estimated and observed concentrations and the Bayesian estimated parameters with the individual final model estimated parameters. RESULTS: The population pharmacokinetic parameters and the inter-subject variablities expressed as coefficient of variation were: the total body clearance CL, 7.1 l h-1 (22%), the volume of the central and peripheral compartments V1, 25.1 l (22.5%), V2, 2.7 l (64%), respectively, and the transfer constant Q, 2.7 (51%) l h-1. Inter-course variability was only significant on CL. Age and serum creatinine had significant effects on CL and was included in the final model. A good correlation was obtained between Bayesian estimated and experimental concentrations (r2=0.85).

[Primitif cerebral lymphoma]. / Lymphomes primitifs du système nerveux central.

Primitif cerebral lymphoma is a rare disease but has increased in incidence over the past decades. Most of them are diffuse B cell lymphomas. An ocular lymphoma (uveitis) is frequently associated. The clinical and radiological features are often suggestive but the diagnostic must be confirmed by histology (either by cerebral biopsy or cytology analysis of the CSF or vitrous). Despite therapeutic advances the prognostic remains poor (median survival range from 3 to 4 years) with frequent recurrences. High dose methotrexate followed by whole brain irradiation is the standard treatment and achieves a high rate of remission but the risk of delayed neurotoxicity is high. This complication is more frequent and severe for patients older than 60 years and chemotherapy alone is usually proposed in elderly people. Immunodeficiency is a contributing factor to the development of primitive cerebral lymphoma; in this setting, differentiating them from infectious lesions (toxoplasmosis in particular) may be difficult. These lymphomas have a poorerprognosis and radiotherapy without chemotherapy is often debated.

Kinetic evaluation of low-grade gliomas in adults before and after treatment with CCNU alone.

OBJECT: The aim of this study was to evaluate the impact of CCNU chemotherapy alone on low-grade glioma (LGG) growth dynamics. METHODS: The authors measured the evolution of the mean tumor diameter (MTD) in adult patients with LGG before (n=28 patients) and after (n=38 patients) CCNU administration. RESULTS: Natural (spontaneous) growth of LGG in the present study was 4.3 mm/year (range 2.1-6.6 mm/year). The median MTD decrease after CCNU was 5.1 mm/year (range 1-8.9 mm/year). MTD decrease was noted in 30 patients (late decrease in 4 patients, and ongoing decrease in 24 patients with oligodendroglial tumors and 2 with astrocytic tumors). The median duration it took for the MTD to decrease after initiation of CCNU treatment was 619 days (1038 days for oligodendroglial tumors vs 377 days for astrocytic tumors; p=0.003). CONCLUSIONS: These results show that CCNU as a single agent has a significant impact on LGG tumor growth. The impact of CCNU seems to be comparable to the previously reported impact of temozolomide therapy and of combined procarbazine, CCNU, and vincristine chemotherapy.

The added value of bevacizumab concomitantly administered with carboplatin versus carboplatin alone in patients with recurrent glioblastomas.

AIMS AND BACKGROUND: Carboplatin (CBDCA) and bevacizumab (BEV) are active in glioblastoma (GBM) with different profiles of toxicity. To date, no study has compared the value of the addition of BEV to historical or traditional cytotoxic chemotherapy. We sought to determine the relative value of BEV in combination with CBDCA versus CBDCA alone in patients with recurrent GBM. METHODS AND STUDY DESIGN: Eligible patients with progressive GBM following surgery, radiotherapy and temozolomide received CBDCA either alone (group 1, n = 25) or in combination with BEV (group 2, n = 23) at 5 mg/kg once every 3 weeks between June 2010 and December 2013. Baseline characteristics and outcomes after treatment were recorded. The primary end points of this retrospective analysis were progression-free survival (PFS) and objective response rate. Secondary end points included safety and overall survival (OS). RESULTS: Forty-eight patients were enrolled. The median number of cycles was 4 in group 1 and 6 in group 2. No toxicities or intracerebral bleeding were observed. The objective response rate was higher in group 2 than group 1, 66% vs 24% (p = 0.003). The estimated median PFS and OS were 3.1 vs 6.7 months (p<0.0001) and 6.1 vs 8.6 months (p = 0.09) in group 1 vs group 2, respectively. CONCLUSIONS: The combination of BEV and CBDCA is associated with improved response rates and survival compared with CBDCA alone. These results highlight the value of BEV in recurrent GBM. However, the clinical benefit of this interesting approach needs validation in a larger patient cohort.

Spinal Dissemination of Intracranial Glioblastoma in Bevacizumab Era: a Potential Bevacizumab-induced Mechanism.

Spinal metastasis, a devastating neurologic complication of intracranial glioblastomas is not as uncommon as initially thought. It varies from 25% in supratentorial glioblastomas to 60% in infratentorial glioblastomas. The underlying pathogenesis spinal spread of high-grade gliomas is still unclear. To date, no causal responsibility of Bevacizumab (BEV) was noted. Here, we report for the first time, a case of thoracic intramedullary metastases from a cerebral glioblastoma pre-treated with BEV. A critical and exhaustive review is provided.

Visual and auditory hallucinations revealing cerebellar extraventricular neurocytoma: uncommon presentation for uncommon tumor in uncommon location.

OBJECTIVE: Visual and auditory hallucinations in relation to a cerebellar tumor are rarely reported in children. Primary origin of extraventricular neurocytoma (EVN) in the cerebellum is very rare. CLINICAL PRESENTATION: We report on a case of a cerebellar EVN in a 13-year-old girl with the initial symptoms of psychiatric manifestations for more than 2 months. Magnetic resonance imaging of the brain revealed a patchy enhanced tumor in the paramedian left cerebellar region. No obstructive hydrocephalus was noted. INTERVENTION: Total surgical removal of the tumor was performed. The tumor was initially diagnosed as an oligodendroglioma. After special immunohistochemical studies, the final definitive diagnosis was an EVN without isocitrate dehydrogenase mutation. CONCLUSION: EVNs located in the cerebellum are extremely rare. We discuss the clinical symptoms and histological-immunohistochemical features of this rare tumor in that rare location.

Bevacizumab alone at 5 mg/kg in an every-3-week schedule for patients with recurrent glioblastomas: a single center experience.

The use of bevacizumab is increasingly reported in neuro-oncology. The most common schedule is 10 mg/kg every 2 weeks. We retrospectively investigated the efficacy of a 3-week schedule of 5 mg/kg bevacizumab in patients with recurrent glioblastomas. Fourteen patients (median age, 46 years) were included in the study. The median number of bevacizumab cycles was 4 (range, 2-8). Five patients (36%) had a partial response, 7 (50%) had stable disease, and 2 (14%) had progressive disease. No grade III-IV toxicities were observed. The median progression-free and overall survival were 3.6 months and 6.4 months, respectively. Every-3-week low-dose single-agent bevacizumab showed substantial activity and a safe profile in patients with recurrent glioblastoma.