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.

Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy.

BACKGROUND: This study was designed to evaluate proton magnetic resonance spectroscopy ((1)H-MRS) for monitoring the WHO grade II glioma (low-grade glioma (LGG)) treated with temozolomide (TMZ). METHODS: This prospective study included adult patients with progressive LGG that was confirmed by magnetic resonance imaging (MRI). Temozolomide was administered at every 28 days. Response to TMZ was evaluated by monthly MRI examinations that included MRI with volumetric calculations and (1)H-MRS for assessing Cho/Cr and Cho/NAA ratios. Univariate, multivariate and receiver-operating characteristic statistical analyses were performed on the results. RESULTS: A total of 21 LGGs from 31 patients were included in the study, and followed for at least n=14 months during treatment. A total of 18 (86%) patients experienced a decrease in tumour volume with a greater decrease of metabolic ratios. Subsequently, five (28%) of these tumours resumed growth despite the continuation of TMZ administration with an earlier increase of metabolic ratios of 2 months. Three (14%) patients did not show any volume or metabolic change. The evolutions of the metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated over time (Spearman ρ=+0.95) and followed a logarithmic regression (P>0.001). The evolutions over time of metabolic ratios, mean(Cho/Cr)(n) and mean(Cho/NAA)(n), were significantly correlated with the evolution of the mean relative decrease of tumour volume, mean(ΔV(n)/V(o)), according to a linear regression (P<0.001) in the 'response/no relapse' patient group, and with the evolution of the mean tumour volume (meanV(n)), according to an exponential regression (P<0.001) in the 'response/relapse' patient group. The mean relative decrease of metabolic ratio, mean(Δ(Cho/Cr)(n)/(Cho/Cr)(o)), at n=3 months was predictive of tumour response over the 14 months of follow-up. The mean relative change between metabolic ratios, mean((Cho/NAA)(n)-(Cho/Cr)(n))/(Cho/NAA)(n), at n=4 months was predictive of tumour relapse with a significant cutoff of 0.046, a sensitivity of 60% and a specificity of 100% (P=0.004). CONCLUSIONS: The (1)H-MRS profile changes more widely and rapidly than tumour volume during the response and relapse phases, and represents an early predictive factor of outcome over 14 months of follow-up. Thus, (1)H-MRS may be a promising, non-invasive tool for predicting and monitoring the clinical response to TMZ.

Supportive care in neurooncology.

The quality of life of patients treated for brain tumor is, in all cases, deeply altered by the tumor and the treatments. Optimizing the symptomatic management is a key objective for all care givers. We present in this paper a very pragmatic focus concerning the management of intracranial hypertension (and/or neurological deficits), venous thromboembolism, confusion, epilepsy and symptoms more directly associated with the end of life.

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma.

BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity.

[Should elderly patients with glioblastoma be proposed to radiotherapy?]. / Faut-il irradier les glioblastomes chez les patients âgés?

In glioblastoma multiform-patients, advanced age has been associated with poor prognosis and decreased tolerance to treatments. The optimal management, especially with irradiation, was not definitively determined in the eighth and ninth decades. The Association of French-speaking neuro-oncologists (Anocef) has recently conducted a randomized clinical trial comparing radiotherapy plus supportive care versus supportive care alone in such patients. Patients aged 70-years and older with newly diagnosed glioblastoma and a Karnofsky performance score of 70 or above were randomly assigned to receive focal irradiation in daily fraction of 1.8 Gy given five days per week for a total dose of 50 Gy plus supportive care or supportive care only. Radiotherapy resulted in a modest but significant improvement in overall survival without reducing quality of life or cognition. However, the optimal regimen of radiotherapy in this fragile population remains uncertain. Abbreviated course of radiotherapy (40 Gy in 15 fractions over 19 days) has been proposed. Analysis of preliminary results showed that efficacy and safety of this hypofractionated accelerated regimen compared favourably with those of classically fractionated treatments. Finally, the potential contribution of surgery and chemotherapy should be evaluated in prospective clinical trials.

Short course of radiation therapy in elderly patients with glioblastoma multiforme.

PURPOSE: The optimal schedule of irradiation in elderly patients suffering from glioblastoma multiforme (GBM) is unsettled. MATERIALS AND METHODS: This study reviewed the charts of 28 consecutive GBM patients aged 70 years or more with a Karnofsky Performance Status (KPS) greater than or equal to 70 who received a short course of radiotherapy (40 grays in 15 fractions over three weeks). RESULTS: The median age at surgery was 74.6 years (range, 70.1-85.7). No patient received prior or concomitant chemotherapy. The median progression-free survival and overall survival were 21.6 weeks (95% CI, 17.0-39.9) and 50.6 weeks (95% CI, 26.3-62.0), respectively. Even within a narrow range (<90 or >or=90), KPS remained a prognostic factor (p=0.03). Tolerance appeared acceptable in terms of KPS changes and corticosteroid use during radiation therapy. CONCLUSION: These results support the efficacy of short schedule radiotherapy for GBM in elderly patients with a good KPS.

[Bevacizumab/irinotecan. An active treatment for recurrent high grade gliomas: preliminary results of an ANOCEF Multicenter Study]. / Bevacizumab/irinotecan. Un nouveau traitement actif dans les gliomes de haut grade récidivants: résultats préliminaires d'une étude multicentrique de l'Anocef.

RATIONALE: Second-line chemotherapy is disappointing in recurrent high-grade gliomas. Dramatic responses in recurrent high-grade gliomas have been reported in a recent monocentric trial with a novel association combining bevacizumab (anti-VEGF monoclonal antibody agent) and irinitecan. OBJECTIVE: To report the experience of the ANOCEF group (French speaking neuro-oncology association) using the bevacizumab-irinotecan combination in recurrent high-grade gliomas. METHODS: Eight centers were involved in this retrospective multicenter study. Bevacizumab-irinotecan was delivered as previously described in a compassional setting to non-selected patients suffering from a high-grade glioma (WHO grade III and IV). Response rate at two months of the onset of the treatment was analyzed using the Macdonald criteria. The toxicity profile of the treatment was also investigated. RESULTS: From 2006 to 2007, 77 patients were treated (median age: 52 years; median Karnofsky score: 70) for a recurrent high-grade glioma (49 grade IV, 28 grade III). At two months, the response rates were objective response=36% (54% in grade III and 27% in grade IV); stable disease=39%; progressive disease=13%; patients not evaluable because of a rapid fatal clinical deterioration=12%. Improvement was noted in 49% of patients. Among the main toxicities, we noted; intratumoral hemorrage (n=5 with spontaneous regression in three) and thromboembolic complications including venous thrombophlebitis (n=4), pulmonary embolism (n=2), myocardial infarction (n=1), grade III-IV hematotoxicity (n=2), reversible leukoencephalopathy (n=1). CONCLUSION: This retrospective multicenter study adds further arguments in favor of the promising results of this new combination and its potential rapidity of action in recurrent high-grade gliomas. Antiangiogenic agents expose the patients to a well-known risk of thromboembolic and hemorragic complications, necessitating careful follow-up and patient selection in light of the cardiovascular contraindications.

[Neoadjuvant chemotherapy followed by radiotherapy adapted to the tumor response in the primary germinoma of the central nervous system: experience of the Pitié-Salpêtrière Hospital and review of literature]. / Chimiothérapie néoadjuvante suivie d'une radiothérapie adaptée à la réponse tumorale dans les tumeurs germinales séminomateuses du système nerveux central: expérience de l'hôpital de la Pitié-Salpêtrière et revue de la littérature.

PURPOSE: Retrospective analysis of ten cases of germinoma of the central nervous system treated in Pitié-Salpêtrière Hospital, Paris. PATIENTS AND METHODS: Ten male patients were treated from 1997 to 2005 for histologically verified primary seminoma of the central nervous system. The median age was 27 years (range 18-40 years). Our option for the treatment was the association of 3-4 cycles of neoadjuvant chemotherapy (cisplatin and etoposide) to radiotherapy. Five patients received a craniospinal radiotherapy of 30 Gy (for one patient 36 Gy) followed by a tumoral boost from 20 to 24 Gy. For five patients, irradiated volume was limited to the tumour, total dose from 24 to 54 Gy (for three patients the total dose was from 24 to 30 Gy). Surgery was used for five patients, but only in one case was macroscopic complete. RESULTS: Six patients were in situation of complete remission after neoadjuvant chemotherapy. All the patients were in situation of complete remission after the irradiation. All the patients were alive free of disease with a median follow-up 46 months (range 13-90 months). CONCLUSION: In spite of the fact that the intracranial germinal tumours are not the subject of a consensual treatment strategy, this retrospective analysis pleads in favour of chemotherapy followed by limited dose and volume irradiation.

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.

Temozolomide as initial treatment for adults with low-grade oligodendrogliomas or oligoastrocytomas and correlation with chromosome 1p deletions.

PURPOSE: To determine the response rate of low-grade oligodendroglial tumors (LGOT) to temozolomide (TMZ) as initial treatment and to evaluate the predictive value of chromosome 1p deletion on the radiologic response. PATIENTS AND METHODS: Adult patients with pathologically proven LGOT with progressive disease on magnetic resonance imaging (MRI) were eligible for the study. TMZ was administered at the starting dose of 200 mg/m2/d for 5 days, repeated every 28 days. Response was evaluated clinically and by central review of MRIs. Chromosome 1p and 19q deletions were detected by the loss of heterozygosity technique. RESULTS: Sixty consecutive patients were included in the study. At the time of analysis, the median number of TMZ cycles delivered was 11. Clinically, 51% of patients improved, particularly those with uncontrolled epilepsy. The objective radiologic response rate was 31% (17% partial response and 14% minor response), whereas 61% of patients had stable disease and 8% experienced disease progression. The median time to maximum tumor response was 12 months (range, 5 to 20 months). Myelosuppression was the most frequent side effect, with grade 3 to 4 toxicity in 8% of patients. Loss of chromosome 1p was associated with objective tumor response (P < .004). CONCLUSION: TMZ is well tolerated and provides a substantial rate of response in LGOT. Chromosome 1p loss is correlated with radiographic response and could be a helpful marker for guiding therapeutic decision making in LGOT.

[Radiotherapy for glioblastomas: from radiobiology to concomitant chemotherapy]. / Radiothérapie des glioblastomes: de la radiobiologie à la chimiothérapie concomitante.

The prognosis of glioblastoma remains extremely poor. Clinical research has been very active for thirty years, and has explored all the concepts developed in the laboratories of radiobiology. Radiosensitisation of hypoxic tumours, hyperfractioned radiotherapy, external beam radiotherapy plus stereotactic radiosurgery or brachytherapy boost, and intensity modulated radiation therapy failed to improve the results of the treatment of these patients. Concomitant chemoradiotherapy has just obtained a new success in the treatment of glioblastoma. The addition of temozolomide to radiotherapy resulted in a statistically significant survival benefit with minimal acute additional toxicity. The challenge remains to improve clinical outcomes further, and some new research pathways are open.

[Gliomatosis cerebri]. / La gliomatose cérébrale.

INTRODUCTION: Gliomatosis cerebri (GC) is defined as a diffuse neoplastic glial cell infiltration of the brain involving more than two cerebral lobes and, occasionally, the infratentorial structures or the spinal cord. The tumor may appear de novo (primary GC) or result from the spreading of a focal glioma (secondary GC). Diagnosis and management of GC are difficult. Because of the diffuse nature of gliomatosis cerebri (GC), surgery is not suitable and large field radiotherapy carries the risk of severe toxicity. STATE OF ART: The analysis of current literature shows that the male population (58 percent) is younger, has a higher incidence of oligodendroglial GC and better prognosis than the female population. Survival (median=14.5 months) is also better for young patients, with high performance status, low-grade gliomatosis, and oligodendroglial subtype. Initial chemotherapy results in nearly 30 percent clinical or radiological improvement. In this setting, temozolomide is well tolerated and appears to be a valuable alternative to procarbazine-CCNU-vincristine, especially for slow-growing, low-grade GC. PERSPECTIVE: Genotyping could be helpful to predict the response to chemotherapy in GC patients.

[Epidemiology of brain metastases]. / Épidémiologie des lésions métastatiques cérébrales.

The most frequent intracranial brain tumours are brain metastases. All types of cancer can develop brain metastases but two thirds of brain metastases occurring in adult patients are secondary to one of these three cancers: lung cancer, breast cancer and melanoma. In accordance with these data, this review is focusing on the epidemiology of these three types of cancer. We report here the incidence, risk factors, median time of brain metastases occurrence after diagnosis of the primary cancer, prognosis and median survival for these three types of cancer. We also discuss the clinical implications of these data. The second part of this review is focusing on the Graded Prognostic Assessment scores in all types of primary cancer with brain metastases, how they can be applied in clinical research for a better stratification of patients, and to some extent in clinical practice to guide decisions for personalized treatments. These scores provide a better understanding of the different profiles of clinical evolution that can be observed amongst patients suffering from brain metastases according to the type of primary cancer. We highlighted the most remarkable and useful clinical implications of these data.

[Systemic treatment of brain metastases from breast cancer]. / Métastases cérébrales de cancer du sein: traitements systémiques.

An increase in the incidence of breast cancer patients with brain metastases has been observed over the last years, mainly because the recent development of new drugs including therapies targeting HER2 (human epidermal growth factor receptor 2) resulted in an increased survival of these patients. With HER2+ patients living longer and the well-known neurotropism of HER2+ tumour cells, the resulting high incidence of brain metastases is not really surprising. Moreover, brain metastases more often occur within a context of existing extracranial metastases. These need to be treated at the same time in order to favourably impact patients' survival. Consequently, the management of breast cancer patients with brain metastases clearly relies on a multidisciplinary approach, including systemic treatment. A working group including neuro-oncologists, neurosurgeons, radiation oncologists and oncologists was created in order to provide French national guidelines for the management of brain metastases within the "Association des neuro-oncologues d'expression française" (ANOCEF). The recommendations regarding the systemic treatment in breast cancer patients are reported here including key features of their management.

[ANOCEF guidelines for the management of brain metastases]. / Recommandations de l'Anocef pour la prise en charge des métastases cérébrales.

The incidence of brain metastases is increasing because of the use of new therapeutic agents, which allow an improvement of overall survival, but with only a poor penetration into the central nervous system brain barriers. The management of brain metastases has changed due to a better knowledge of immunohistochemical data and molecular biological data, the development of new surgical, radiotherapeutic approaches and improvement of systemic treatments. Most of the time, the prognosis is still limited to several months, nevertheless, prolonged survival may be now observed in some sub-groups of patients. The main prognostic factors include the type and subtype of the primitive, age, general status of the patient, number and location of brain metastases, extracerebral disease. The multidisciplinary discussion should take into account all of these parameters. We should notice also that treatments including surgery or radiotherapy may be proposed in a symptomatic goal in advanced phases of the disease underlying the multidisciplinary approach until late in the evolution of the disease. This article reports on the ANOCEF (French neuro-oncology association) guidelines. The management of brain metastases of breast cancers and lung cancers are discussed in the same chapter, while the management of melanoma brain metastases is reported in a separate chapter due to different responses to the brain radiotherapy.

[Global brain metastases management strategy: a multidisciplinary-based approach]. / Stratégie globale de prise en charge des métastases cérébrales: une approche multidisciplinaire.

Brain metastases management has evolved over the last fifteen years and may use varying strategies, including more or less aggressive treatments, sometimes combined, leading to an improvement in patient's survival and quality of life. The therapeutic decision is subject to a multidisciplinary analysis, taking into account established prognostic factors including patient's general condition, extracerebral disease status and clinical and radiological presentation of lesions. In this article, we propose a management strategy based on the state of current knowledge and available therapeutic resources.

[Supportive care, cognition and quality of life in brain metastases]. / Soins de support, cognition, qualité de vie et métastases cérébrales.

Brain metastases impact on the survival of the patients, but on their quality of life as well. The objective of the management of these patients is then double. Currently, due to medical advances, survivals tend to improve, especially for some tumor subtypes. During the course of the disease, different neurological signs and symptoms can be observed according to the location, the number and the volume of the metastase(s). Patients and caregivers are especially worried about the loss of autonomy and cognitive impairments. A permanent dialogue, during the course of the disease, is mandatory, in order to adapt the management to the objectives determined by the patients and the medical team. These objectives may vary according to the objective response rates of the disease to anticancer therapies, according to the impact of the disease and its management in daily living. Anticancer therapies and supportive care must be appreciated according to their impact on the survival, on the preservation of the functional independence and the quality of life of the patient, on their abilities to preserve the neurological status and delay the apparition of new neurological signs and symptoms, and their adverse events. Supportive care, cognition and quality of life should be regularly evaluated and adapted according to the objectives of the management of brain metastases patients. Different approaches are described in this paper.

Hibernoma, an uncommon tumor as a differential diagnosis of liposarcoma of the thigh.

Hibernomas are benign tumors derived from brown fat of hibernating animals and of human infants. The pathogenesis and malignant potential of hibernomas remain unclear. They occur generally in adults with a peak incidence in the third decade and with a predominance in women. However, the lesions may have an heterogeneous presentation that may mimic liposarcomas on MRI. Our report presents a case of hibernoma of the thigh whose the diagnosis initially suggested that it was a mixed liposarcoma with myxoid and well differentiated components.

A mesocolic leiomyosarcoma metastatic to the breast: case report and review of the literature.

This report describes a patient with mesocolic leiomyosarcoma, initially treated by excisional surgery. One year later the patient developed breast and hepatic metastases. To our knowledge, metastasis of leiomyosarcoma to the breast has not been previously reported in the literature. The discussion covers unusual sites for metastases of primary leiomyosarcomas and those tumors that most commonly give rise to breast metastases. Certain rare primary tumors of the breast related to the family of sarcomas are also brought to the attention of the reader. These may or may not have malignant characteristics. In the light of the differences in prognosis and treatment, recognition and precise diagnosis is of importance.