Current trends in the management of glioblastoma in a French University Hospital and associated direct costs.

WHAT IS NEW AND OBJECTIVES: Trends in the care of glioblastoma in actual practice settings are poorly described. In a previous pharmacoepidemiologic study, we highlighted changes in the management of patients with glioblastoma (GBM) newly diagnosed between 2004 and 2008. Our aim was to complete and to extend the previous report with a study of a cohort of patients diagnosed in 2011 to emphasize the trends in the pharmacotherapy of GBM over the last decade. METHODS: A single-centre study was undertaken of three historic cohorts of GBM patients newly diagnosed during years 2004, 2008 and 2011 (corresponding to groups 1, 2 and 3, respectively) but limited to patients eligible for radiotherapy after initial diagnosis. The type of medical management was described and compared, as well as overall survival and total cost from diagnosis to death or the last follow-up date. Cost analysis was performed from the French sickness fund perspective using tariffs from 2014. RESULTS: Two hundred and seventeen patients (49 in Group 1, 73 in Group 2, 95 in Group 3) were selected with similar baseline characteristics. Fluorescence-guided surgery using 5-ALA was increasingly used over the three periods. There was a strong trend towards broader use of temozolomide radiochemotherapy (39%, 73% and 83% of patients, respectively) as first-line treatment as well as bevacizumab regimen at recurrence (6%, 48% and 58% of patients, respectively). The increase in overall survival between Group 2 and Group 1 was confirmed for patients in Group 3 (17·5 months vs. 10 months in Group 1). The mean total cost per patient was 53368 € in Group 1, 70 201 € in Group 2 and 78355 € in Group 3. Hospital care represented the largest expenditure (75%, 59% and 60% in groups 1, 2 and 3, respectively) followed by chemotherapy drug costs (11%, 30% and 29%, respectively). WHAT IS NEW AND CONCLUSION: This is the first study to report on changes in the management of GBM in real-life practice. The ten-year study indicates an improvement in overall survival but also an increase in total cost of care. The data should be useful for informing the care of GBM patients in settings similar to ours.

Management of glioblastoma: comparison of clinical practices and cost-effectiveness in two cohorts of patients (2008 versus 2004) diagnosed in a French university hospital.

WHAT IS KNOWN AND OBJECTIVE: Therapeutic options for the management of glioblastoma (GBM) have greatly evolved over the last decade with the emergence of new regimens combining radiotherapy plus temozolomide and the use of bevacizumab at recurrence. Our aim was to assess the clinical and economic impacts of those novel strategies in our center. METHODS: A single-center retrospective chart review was conducted on patients newly diagnosed with a GBM over two periods (year 2004, group 1 or year 2008, group 2) with limitations to those eligible to radiotherapy after initial diagnosis. The type of medical management was described and compared, as well as overall survival and total costs from diagnosis to death or the last follow-up date. Cost analysis was performed under the French Sickness Fund perspective using tariffs from 2012. RESULTS: One hundred twenty-two patients were selected (49 in group 1 and 73 in group 2) with similar baseline characteristics within the two groups. Patients from group 2 received more frequently temozolomide radiochemotherapy (71% vs. 39%, P < 0·05) as first-line treatment as well as bevacizumab regimen at recurrence (48% vs. 6%, P < 0·05); the median overall survival was increased between the two periods (respectively 17 vs. 10 months, P < 0·05). The mean total cost per patient was 54,388 € in group 1 and 71,148 € in group 2 (P < 0·05). Hospital care represented the largest expenditure (76% and 58% in groups 1 and 2 respectively) followed by chemotherapy drugs costs (11% and 30% respectively). The total cost difference between the two groups was explained by the increasing use of temozolomide and bevacizumab. The incremental cost-effectiveness ratio was estimated at 54,355 € per life-year gained. WHAT IS NEW AND CONCLUSION: As far as we know, this is the first study reporting the total cost of GBM management based on the French perspective, as well as the cost-effectiveness of clinical practices in term of cost per life-year gained. Those novel strategies have contributed to improve overall survival while inducing a substantial, but acceptable, increase of total costs.

Patterns of care and survival of glioblastoma patients: a comparative study between 2004 and 2008 in Lyon, France.

INTRODUCTION: The treatment of glioblastomas (GBMs) has changed significantly since 2005. However, the extent to which this change has improved overall survival (OS) of patients treated outside clinical trials remains to be determined. METHODS: We compared the patterns of care and OS of all GBM patients diagnosed in 2004 (n=105) and in 2008 (n=130) in our center. RESULTS: Younger patients (aged<70 years) diagnosed in 2008 received temozolomide radiochemotherapy as the initial treatment and bevacizumab at recurrence more frequently than those diagnosed in 2004 (69% vs 26% P<10(-4) and 41% vs 3%, P<10(-4), respectively). Elderly patients (aged≥70 years) diagnosed in 2008 received an oncological treatment (radiotherapy and/or chemotherapy) more frequently than those diagnosed in 2004 (67% vs 38%, P=0.006). The patients diagnosed in 2008 had longer OS than those diagnosed in 2004 (10.5 months vs 5.3 months, P=0.001). This finding was true for both younger and elderly patients (15.3 months vs 8.9 months, P=0.02 and 6.4 months vs 3.2 months, P=0.0002, respectively) and when considering only IDH1 wild-type patients (8.9 months vs 5.3 months, P=0.004). CONCLUSION: In our center, the change in the patterns of care for GBMs between 2004 and 2008 has been associated with a significant improvement in OS.

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.

Onco-neural antibodies and tumour type determine survival and neurological symptoms in paraneoplastic neurological syndromes with Hu or CV2/CRMP5 antibodies.

OBJECTIVE: Anti-Hu antibodies (Hu-Ab) and anti-CV2/CRMP5 antibodies (CV2/CRMP5-Ab) have been identified in association with paraneoplastic neurological disorders. However, it is not clear whether these antibodies are associated with specific neurological symptoms or are only markers of anti-cancer immune reaction. METHODS: To address this question, 37 patients with CV2/CRMP5-Ab and 324 patients with Hu-Ab were compared. RESULTS: Whereas the age and sex ratio were the same between the two groups, the distribution of neurological symptoms was not. Patients with CV2/CRMP5-Ab presented more frequently cerebellar ataxia, chorea, uveo/retinal symptoms and myasthenic syndrome (Lambert-Eaton myasthenic syndrome LEMS or myasthenia gravis). They also had a better Rankin score. In contrast, dysautonomia, brainstem encephalitis and peripheral neuropathy were more frequent in patients with Hu-Ab. Limbic encephalitis occurred similarly in both groups. Small-cell lung cancer was the most frequently associated tumour in both groups of patients, while malignant thymoma was observed only in patients with CV2/CRMP5-Ab. In particular, patients with CV2/CRMP5-Ab and thymoma developed myasthenic syndrome more frequently, while patients with SCLC developed neuropathies more frequently. Chorea and myasthenic syndrome were only seen in patients with CV2/CRMP5-Ab. The median survival time was significantly longer in patients with CV2/CRMP5-Ab, and this effect was not dependent on the type of tumour. INTERPRETATION: The data demonstrate that in patients with paraneoplastic neurological syndromes, the neurological symptoms and survival vary with both the type of associated onco-neural antibody and the type of tumour.

[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.

[Supervision of low-grade gliomas with multiparametric MR imaging: research of radiologic indicators of malignancy transformation]. / Intérêt de l'IRM, avec séquences de diffusion, de perfusion et de la spectrométrie dans le diagnostic et la surveillance de gliomes d'aspect initial de grade 2 : recherche de marqueurs radiologiques orientant vers une aggravation tumorale de grade.

We assessed the contribution of diffusion, perfusion and spectroscopy imaging for the diagnosis and follow-up of intraaxial tumors, suspected to be grade II gliomas. Twenty-four patients were included from April 2005 to July 2006, 17 initially and seven during their follow-up. The diagnosis was reconsidered in a first group of six patients: a high-grade tumor was suspected and confirmed in five. These patients presented a lipid peak; the perfusion results and the CHO/Cr and CHO/NAA ratios were not pathological. The second group included patients with grade II gliomas: these 18 patients had a radiographic work-up, initially, then at three months and every six months. For this group, no evidence of a change of grade were observed. Abnormal findings were noted in seven patients: among these patients, one developed radiographic progression, one other had radiographic progression associated with a spectroscopy lipid peak; only spectroscopy changes were noted in the third patient; the last patient had radiographic progression with perfusion and spectroscopy abnormalities; these four patients were treated. These observations suggest that diffusion, perfusion and spectroscopy can provide supplementary information for diagnosis and follow-up of glial tumors. The presence of a lipid peak is of particular value. The limitations of this work must also be taken into consideration: the follow-up was too short for slow-growing gliomas; the population was small and patients may have undergone surgery during the study, leading to structural modifications which may have compromised comparisons. This work should be continued with new examinations every six months and inclusion of new patients.

[Long-term outcome in patients with symptomatic low-grade oligodendrogliomatous tumors treated by cytotoxic agents]. / Effets à long terme de la chimiothérapie chez 7 patients présentant un gliome de bas grade symptomatique.

INTRODUCTION: Whether aggressive treatment or no treatment is the optimal management for low-grade gliomas is controversial. However, symptomatic low-grade gliomas require prompt therapeutic intervention because of neurological impairment, uncontrolled seizures, and deterioration of life quality. METHODS: We report the long-term follow-up, 71 months, of seven patients treated by procarbazine, lomustine and vincristine (PCV) therapy for a symptomatic low-grade oligodendrogliomatous tumor. The mean age at diagnosis was 47 years, the mean time from first symptoms to initiation of PCV therapy was 62 months (range 15-147). RESULTS: All patients initially responded favorably, with improvement of the neurological symptoms and radiological response. Chemotherapy was clinically well tolerated, the main side effect being low hematological toxicity. During the follow-up, no progression was observed in two patients. For the five remaining patients, the time to progression after the PCV induction was 56+/-12 months (range 38 to 73). Four of these patients showed favorable response to a second line of treatment. CONCLUSION: PCV therapy is an interesting therapeutic option for progressively symptomatic low-grade gliomas, even in cases with large tumoral volume. This treatment, of moderate toxicity, improves the quality of life and can result in long-term tumor stabilization.

[Management of malignant gliomas diagnosed during pregnancy]. / Prise en charge des gliomes malins découverts au cours d'une grossesse.

INTRODUCTION: Glioma is seldom diagnosed during pregnancy. In this situation management presents difficult problems for both neuro-oncologists and obstetricians. We report four cases and discuss the management of this unusual situation. CASE REPORT: The first patient was admitted to hospital at 29 weeks' gestation because of a generalized seizure and a right hemiparesis. MRI showed a left fronto-insular lesion. A stereotactic biopsy was obtained and revealed an anaplastic oligodendroglioma. With corticosteroids the patient remained stable until cesarean delivery at 36 weeks. In post-partum additional treatment with chemotherapy was started. The second patient was hospitalized at 26 weeks' gestation because of cranial hypertension, right hemiparesis and aphasia. MRI showed an important left fronto-parietal lesion. Partial resection was performed at 28 weeks. Histology revealed a glioblastoma multiforme. With corticosteroids the patient remained stable until cesarean delivery at 33 weeks. In post-partum additional treatment with radiotherapy and chemotherapy was started. The third patient was admitted to the hospital at 12 weeks' gestation because of cranial hypertension. MRI showed a left frontal lesion. A subtotal resection was done at 13 weeks. Histology revealed a glioblastoma multiforme. Two weeks after surgery the patient's neurological condition worsened and in agreement with the patient a therapeutic abortion was decided. Afterwards additional treatment with radiotherapy and chemotherapy was started. The last patient received combined treatment with radiotherapy and chemotherapy for local recurrence of a mesencephalic high-grade glioma. A posteriori it was discovered that the patient was at 4 months' gestation during this treatment. Cesarean delivery was done at 36 weeks. The child was normal at birth and is still in good health 5 years later. CONCLUSION: The management of gliomas diagnosed during pregnancy should not be different from the standard management of gliomas in young non-pregnant adults. Pregnant women because of their young age can have a long survival. Their pregnancy should not prevent them from receiving the best treatment for their glioma. Treatment will depend upon clinico-radiological presentation, histology, gestational age and the patient's desires. Generally speaking, surgical resection of high-grade gliomas should not be delayed during pregnancy. Progress in anesthesia and neurosurgery have greatly reduced the risks for the foetus. After delivery, if the delay between surgery and delivery is too long it is possible to begin cerebral radiotherapy during pregnancy. After the first trimester of gestation this treatment can be given without any important risks for the child.

[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.

[Place of chemotherapy and radiotherapy in the management of oligodendrogliomas]. / Place de la chimiothérapie et de la radiothérapie dans le traitement des oligodendrogliomes.

Twenty years ago, the discovery of the chemosensitivity of anaplastic oligodendrogliomas considerably boosted interest for these tumors. In spite of difficulties for histological diagnosis, numerous studies on radiotherapy and chemotherapy for oligodendrogliomas appeared these last years. They allowed to detail the appropriate role for these therapeutics. For low grade oligodendrogliomas, radiotherapy delays the anaplastic transformation, but does not modify the overall survival; its indication has to be discussed particularly in the absence of clinical symptoms. Chemotherapy seems to be effective for low grade oligodendrogliomas as well as anaplastic tumors. However, phase III studies are necessary to clarify the contribution of chemotherapy for the treatment of low grade oligodendrogliomas, mainly in relation to radiotherapy. In anaplastic oligodendrogliomas, in spite of the lack of phase III studies, radiotherapy seems to be effective. Chemotherapy is clearly effective, but the most appropriate timing (neoadjuvant, adjuvant, at recurrence) is unknown. Results of current prospective studies are awaited. Recently, molecular genetic analysis, particularly the loss of 1p and 19q chromosomes appears to demonstrate a genetic influence on both prognosis and response to treatment.

[Chronic meningitis before diagnosis of celiac disease]. / Méningite chronique précédant la découverte d'une maladie coeliaque.

Neurological complications, mainly cerebellar syndrome, have been associated with coeliac disease. We report the first observation of a 56-year-old woman with a chronic meningitis revealing coeliac disease. Neuralgia of the trijeminal nerve and cerebellar syndrome only appeared seven years after the onset of meningitis. MRI examination showed a cerebellar atrophy and a leucoencephalopathy. This case report emphasizes the utility of detection of anti-gliadin antibodies for the diagnosis of a chronic meningitis.

[Prescription guidebook for temozolomide usage in brain tumors]. / Guide de prescription et de bon usage du témozolomide dans les tumeurs cérébrales.

Malignant gliomas are the most frequent primary brain tumors in adults. Temozolomide is an oral alkylating cytotoxic agent of second generation, used in the treatment of high-grade gliomas. It is indicated in newly diagnosed glioblastoma multiform as well as in recurrent or progressive malignant gliomas, such as glioblastoma multiform or anaplastic astrocytoma. However, temozolomide is also used, off label, in other clinical situations and the main objective of this study was to establish recommendations and guidelines for relevant prescriptions of temozolomide in primary brain tumors and brain metastasis in adults. The literature review was analysed by experts who determined the evidence level (A to E) according to the scale of recommendations adopted by the "Haute Autorité de santé--HAS--(French National Authority for Health)". For high-grade and low-grade gliomas, based on the level of evidence from the literature, the use of temozolomide can be justified, with a B2 score attributed to these indications. In contrast, for the others indications, the use of temozolomide appeared to be more controversial or even not recommended (score C to E). Regarding the dosing schedule and administration scheme, as well as the co-administration with other anticancer drugs, a C score was attributed for the off label situations.

Initial chemotherapy in gliomatosis cerebri.

BACKGROUND: Because of the diffuse nature of gliomatosis cerebri (GC), surgery is not suitable, and large field radiotherapy carries the risk of severe toxicity. In this setting, initial chemotherapy warrants further investigation. METHODS: The authors treated 63 consecutive patients with GC with initial chemotherapy consisting of either PCV (procarbazine, 60 mg/m2 on days 8 to 21; CCNU, 110 mg/m2 on day 1; and vincristine, 1.4 mg/m2 on days 8 and 29) or temozolomide (TMZ; 150 to 200 mg/m2 for 5 days every 4 weeks). There were 40 men and 23 women, with a median age of 48 years (range, 17 to 74 years) and a median Karnofsky performance status of 90 (range, 50 to 100). GC was initially present at diagnosis in 49 patients (primary GC), whereas 14 patients with a circumscribed glioma at onset developed secondary GC after a median follow-up period of 5.11 years. GC was classified based on the predominant tumor cells as astrocytic, oligodendroglial, or mixed GC. RESULTS: Seventeen patients received 1 to 6 cycles (median, 5) of PCV, and 46 received 2 to 24 courses (median, 13) of TMZ. Grade 3 to 4 hematologic toxicity was seen in 4 of 17 (23.5%) patients treated with PCV and in 4 of 46 (8.6%) of those treated with TMZ. Clinical objective responses were observed in 21 of 63 (33%) patients, and radiologic responses were seen in 16 of 62 (26%), with no significant difference between the two regimens. For all patients combined, the median progression-free survival (PFS) and overall survival (OS) were 16 months and 29 months, respectively. Regardless of the chemotherapeutic regimen, oligodendroglial GC had a better prognosis than astrocytic and oligoastrocytic GC in terms of PFS (p < 0.02) and OS (p < 0.0001). CONCLUSION: Initial chemotherapy is useful for some patients with gliomatosis cerebri. Temozolomide is well tolerated and appears to be a valuable alternative to procarbazine-CCNU-vincristine, especially for those with slow-growing, low-grade GC.