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.

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.

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.

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.

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.

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.

A tumor growth inhibition model for low-grade glioma treated with chemotherapy or radiotherapy.

PURPOSE: To develop a tumor growth inhibition model for adult diffuse low-grade gliomas (LGG) able to describe tumor size evolution in patients treated with chemotherapy or radiotherapy. EXPERIMENTAL DESIGN: Using longitudinal mean tumor diameter (MTD) data from 21 patients treated with first-line procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea, and vincristine (PCV) chemotherapy, we formulated a model consisting of a system of differential equations, incorporating tumor-specific and treatment-related parameters that reflect the response of proliferative and quiescent tumor tissue to treatment. The model was then applied to the analysis of longitudinal tumor size data in 24 patients treated with first-line temozolomide (TMZ) chemotherapy and in 25 patients treated with first-line radiotherapy. RESULTS: The model successfully described the MTD dynamics of LGG before, during, and after PCV chemotherapy. Using the same model structure, we were also able to successfully describe the MTD dynamics in LGG patients treated with TMZ chemotherapy or radiotherapy. Tumor-specific parameters were found to be consistent across the three treatment modalities. The model is robust to sensitivity analysis, and preliminary results suggest that it can predict treatment response on the basis of pretreatment tumor size data. CONCLUSIONS: Using MTD data, we propose a tumor growth inhibition model able to describe LGG tumor size evolution in patients treated with chemotherapy or radiotherapy. In the future, this model might be used to predict treatment efficacy in LGG patients and could constitute a rational tool to conceive more effective chemotherapy schedules.

Insights on the natural history and pathogenesis of multilevel discal cysts.

Discal cysts are rare lesions and uncommon causes of low back pain and radiculopathy. Despite growing evidence regarding the clinical, pathological and radiological presentation of these lesions, we do not yet have a detailed understanding of their natural history, etiology or pathogenesis. To our knowledge this is the first report of multiple and multilevel discal cysts, and possible mechanisms of pathogenesis are proposed.

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.

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.

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.

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.

Chromosome 9p and 10q losses predict unfavorable outcome in low-grade gliomas.

The loss of chromosomes 1p-19q is the only prognostic molecular alteration identified in low-grade gliomas (LGGs) to date. Search for loss of heterozygosity (LOH) on chromosomes 1p, 9p, 10q, and 19q was performed in a series of 231 LGGs. Loss of chromosomes 1p-19q was strongly correlated with prolonged progression-free survival (PFS) and overall survival (OS) in univariate and multivariate analyses. LOH on 9p and 10q were associated with shortened PFS (P = .01 and .03, respectively) on univariate analysis. On multivariate analysis, LOH on 9p remained significant for PFS (P = .05), whereas LOH on 10q had a significant effect on OS (P = .02). Search for LOH 9p and 10q appears to be a useful complement to analysis of chromosomes 1p-19q in LGGs.