Chantal Campello

Temozolomide in Elderly Patients With Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial

PURPOSE The management of glioblastoma multiforme (GBM) in elderly patients with poor performance status is not well established. A trial evaluating the efficacy and safety of temozolomide alone in this population was undertaken. PATIENTS AND METHODS Patients age 70 years or older with newly diagnosed GBM and postoperative Karnofsky performance score (KPS) less than 70 were eligible for this nonrandomized phase II trial. Treatment consisted of 150 to 200 mg/m(2)/d temozolomide for 5 days every 4 weeks until disease progression. Radiotherapy was not administered. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, quality of life, and cognition. RESULTS Seventy patients (median age, 77 years; median KPS, 60) were enrolled between July 2007 and February 2009. Grade 3 to 4 neutropenia and thrombocytopenia occurred in 13% and 14% of patients, respectively. Median PFS was 16 weeks (95% CI, 10 to 20 weeks), and median OS was 25 weeks (95% CI, 19 to 28 weeks), comparing favorably with a 12- to 16-week OS expected from a purely supportive approach. Twenty-three patients (33%) improved their KPS by 10 or more points, and 18 (26%) became capable of self-care (KPS ≥ 70). Overall quality of life and cognition improved over time before disease progression. In the 31 tumors evaluated for O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation, a methylated status indicated longer PFS (26 v 11 weeks; P = .03) and OS (31 v 19 weeks; P = .03). CONCLUSION Temozolomide has an acceptable tolerance in elderly patients with GBM and KPS less than 70. It is associated with improvement of functional status in 33% of patients and appears to increase survival compared with supportive care alone, especially in patients with methylated MGMT promoter.

Oncological patterns of care and outcome for 952 patients with newly diagnosed glioblastoma in 2004

This report, an audit requested by the French government, describes oncological patterns of care, prognostic factors, and survival for patients with newly diagnosed and histologically confirmed glioblastoma multiforme (GBM) in France. The French Brain Tumor DataBase, which is a national multidisciplinary (neurosurgeons, neuropathologists, radiotherapists, neurooncologists, epidemiologists, and biostatisticians) network, prospectively collected initial data for the cases of GBM in 2004, and a specific data card was used to retrospectively collect data on the management and follow-up care of these patients between January 1, 2004, and December 1, 2006. We recorded 952 cases of GBM (male/female ratio 1.6, median age 63.9 years, mean preoperative Karnofsky performance status [KPS] 79). Surgery consisted of resection (RS; n = 541) and biopsy (n = 411); 180 patients did not have subsequent oncological treatment. After surgery, first-line treatment (n = 772) consisted of radiotherapy (RT) and temozolomide (TMZ) concomitant +/- adjuvant in 314 patients, RT alone in 236 patients, chemotherapy (CT) alone in 157 patients, and other treatment modalities in 65 patients. Median overall survival was 286 days (95% CI, 266-314) and was significantly affected by age, KPS, and tumor location. Median survival (days, 95% CI) associated with these main strategies, when analyzed by a surgical group, were as follows: RS + RT-TMZ((n=224)): 476 (441-506), biopsy + RT-TMZ((n=90)): 329 (301-413), RS + RT((n=147)): 363 (331-431), biopsy + RT((n=89)): 178 (153-237), RS + CT((n=61)): 245 (190-361), biopsy + CT((n=96)): 244 (198-280), and biopsy only((n=118)): 55 (46-71). This study illustrates the usefulness of a national brain tumor database. To our knowledge, this work is the largest report of recent GBM management in Europe.

An MRI review of acquired corpus callosum lesions

Lesions of the corpus callosum (CC) are seen in a multitude of disorders including vascular diseases, metabolic disorders, tumours, demyelinating diseases, trauma and infections. In some diseases, CC involvement is typical and sometimes isolated, while in other diseases CC lesions are seen only occasionally in the presence of other typical extra-callosal abnormalities. In this review, we will mainly discuss the MRI characteristics of acquired lesions involving the CC. Identification of the origin of the CC lesion depends on the exact localisation of the lesion(s) inside the CC, presence of other lesions seen outside the CC, signal changes on different MRI sequences, evolution over time of the radiological abnormalities, history and clinical state of the patient, and other radiological and non-radiological examinations.

Thalamic Lesions: A Radiological Review

Background. Thalamic lesions are seen in a multitude of disorders including vascular diseases, metabolic disorders, inflammatory diseases, trauma, tumours, and infections. In some diseases, thalamic involvement is typical and sometimes isolated, while in other diseases thalamic lesions are observed only occasionally (often in the presence of other typical extrathalamic lesions). Summary. In this review, we will mainly discuss the MRI characteristics of thalamic lesions. Identification of the origin of the thalamic lesion depends on the exact localisation inside the thalamus, the presence of extrathalamic lesions, the signal changes on different MRI sequences, the evolution of the radiological abnormalities over time, the history and clinical state of the patient, and other radiological and nonradiological examinations.

Coping with a newly diagnosed high-grade glioma: patient-caregiver dyad effects on quality of life.

Patients with high-grade gliomas (HGG) and their caregivers have to confront a very aggressive disease that produces major lifestyle disruptions. There is an interest in studying the ability of patients and their caregivers to cope with the difficulties that affect quality of life (QoL). We examine, in a sample of patient-caregiver dyads in the specific context of newly diagnosed cases of HGG, whether the QoL of patients and caregivers is influenced by the coping processes they and their relatives use from a specific actor–partner interdependence model (APIM). This cross-sectional study involved 42 dyads with patients having recent diagnoses of HGG and assessed in the time-frame between diagnosis and treatment initiation. The self-reported data included QoL (Patient-Generated Index, EORTC QLQ-C30, and CareGiver Oncology QoL), emotional status, and coping strategies (BriefCope). The APIM was used to test the dyadic effects of coping strategies on QoL. Coping strategies, such as social support, avoidance, and problem solving, exhibited evidence of either an actor effect (degree to which the individual’s coping strategies are associated with their own QoL) or partner effect (degree to which the individual’s coping strategies are associated with the QoL of the other member of the dyad) for patients or caregivers. For positive-thinking coping strategies, actor and partner effect were not observed. This study emphasizes that the QoL for patients and their caregivers was directly related to the coping strategies they used. This finding suggests that targeted interventions should be offered to help patients and their relatives to implement more effective coping strategies.

Prognostic value of health-related quality of life for death risk stratification in patients with unresectable glioblastoma.

Glioblastoma is the most common malignant brain tumor in adults. Baseline health‐related quality of life (HRQoL) is a major subject of concern for these patients. We aimed to assess the independent prognostic value of HRQoL in unresectable glioblastoma (UGB) patients for death risk stratification. One hundred and thirty‐four patients with UGB were enrolled from the TEMAVIR trial. HRQoL was evaluated at baseline using the EORTC QLQ‐C30 and BN20 brain cancer module. Clinical and HRQoL parameters were evaluated in univariable and multivariable Cox analysis as prognostic factors for overall survival (OS). Performance assessment and internal validation of the final model were evaluated with Harrels C‐index, calibration plot, and bootstrap sample procedure. Two OS independent predictors were identified: future uncertainty and sensitivity deficit. The final model exhibited good calibration and acceptable discrimination (C statistic = 0.63). The internal validity of the model was verified with robust uncertainties around the hazard ratio. The prognostic score identified three groups of patients with distinctly different risk profiles with median OS estimated at 16.2, 9.2, and 4.5 months. We demonstrated the additional prognostic value of HRQoL in UGB for death risk stratification and provided a score that may help to guide clinical management and stratification in future clinical trials.

Globus pallidus and substantia nigra hypointensities on T2*-weighted imaging in MELAS

We present a 48-year-old mother [with history of seizures, migraine, diabetes mellitus, neurosensory hearing loss, short stature, cognitive deficit, and ataxia, and onset of stroke-like episodes 3 years after initial magnetic resonance imaging (MRI)] and her 20-year-old son (with history of one strokelike episode at the moment of the initial MRI, and another stroke-like episode 3 months later, in absence of other signs) with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS, m.3243A [G tRNALeu[UUR] mutation), both showing on computed tomography (CT) bipallidal microcalcifications and on initial 3-T T2*-weighted MRI (TE = 13 ms, TR = 475 ms) large bilateral hypointensities in the pallidum and the substantia nigra (Fig. 1). Basal ganglia showed normal intensities on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging, and very slight hypointense (i.e., nearnormal) signal on T2-weighted imaging (Fig. 1). One strokelike lesion (accompanying stroke-like symptoms) was seen on initial MRI in the son, and another stroke-like lesion occurred 3 months later, and the mother presented strokelike lesions 3 years after the initial MRI (Fig. 2). Both patients also showed cerebral and cerebellar atrophy, and slight bilateral posterior leukoencephalopathy on MRI (Fig. 2). MRI follow-up (3 years in the mother, and 3 months in the son) did not show evolution of the T2*-weighted hypointensities in the pallidum and the substantia nigra. Radiological abnormalities (sometimes absent or discrete, especially in the early stage of the disease) encountered in MELAS include cerebral and cerebellar atrophy, basal ganglia signal changes, stroke-like lesions, and leukodystrophy. Extensive calcifications are the most frequently encountered basal ganglia abnormalities in MELAS, most frequently described on CT and only rarely on MRI in the literature [1]. Basal ganglia calcifications in our two patients were discrete on CT. The extent of the MRI abnormalities, when compared with CT, may be explained by the magnetic susceptibility effect of T2*weighted imaging (potentially exaggerated by the highfield 3-T MRI used in our patients) and/or the presence of microscopic calcium and iron deposition [2, 3]. Both calcium and iron deposition in the globus pallidus have been demonstrated earlier on autopsy in MELAS [2]. T2and diffusion-weighted MRI changes and necrotizing lesions on autopsy have been reported in the substantia nigra in another mitochondrial syndrome, i.e., Leigh syndrome [4, 5]. In a general population, incidence of basal ganglia calcifications on CT scan varies between 0.6 and 0.8 % [6, 7]. Incidence increases with increasing age [7, 8]. In the elderly, basal ganglia calcifications are encountered in 38.7 % of patients on CT scan, with the globus pallidus as the most frequently involved structure [9]. The precise agematched incidence, the MRI-based incidence of age-related basal ganglia calcifications, and the pathophysiology explaining the predominant involvement of certain substructures (e.g., the pallidum in our MELAS patients and in the elderly) are unknown. When MELAS is suspected clinically, T2*-weighted MRI imaging (and thus not only CT scan) may be an interesting additional radiological tool to detect discrete calcium and/or iron deposition, especially in young patients (in whom age-related basal ganglia calcifications are less D. Renard (&) C. Campello A. Le Floch G. Castelnovo G. Taieb Department of Neurology, CHU Nimes, Hopital Caremeau, Place du Pr Debre, 30029 Nimes Cedex 4, France e-mail: dimitrirenard@hotmail.com

Temozolomide Plus Bevacizumab in Elderly Patients with Newly Diagnosed Glioblastoma and Poor Performance Status: An ANOCEF Phase II Trial (ATAG)

Abstract Lessons Learned. Results suggest that the combination of bevacizumab plus temozolomide is active in terms of response rate, survival, performance, quality of life, and cognition in elderly patients with glioblastoma multiforme with poor performance status. Whether this combination is superior to temozolomide alone remains to be demonstrated by a randomized study. Background. The optimal treatment of glioblastoma multiforme (GBM) in patients aged ≥70 years with a Karnofsky performance status (KPS) <70 is not established. This clinical trial evaluated the efficacy and safety of upfront temozolomide (TMZ) and bevacizumab (Bev) in patients aged ≥70 years and a KPS <70. Materials and Methods. Patients aged ≥70 years with a KPS <70 and biopsy‐proven GBM were eligible for this multicenter, prospective, nonrandomized, phase II trial of older patients with impaired performance status. Treatment consisted of TMZ administered at 130–150 mg/m2 per day for 5 days every 4 weeks plus Bev administered at 10 mg/kg every 2 weeks. Results. The trial included 66 patients (median age of 76 years; median KPS of 60). The median overall survival (OS) was 23.9 weeks (95% confidence interval [CI], 19–27.6), and the median progression‐free survival (PFS) was 15.3 weeks (95% CI, 12.9–19.3). Twenty‐two (33%) patients became transiently capable of self‐care (i.e., KPS >70). Cognition and quality of life significantly improved over time during treatment. Grade ≥3 hematological adverse events occurred in 13 (20%) patients, high blood pressure in 16 (24%), venous thromboembolism in 3 (4.5%), cerebral hemorrhage in 2 (3%), and intestinal perforation in 2 (3%). Conclusion. This study suggests that TMZ + Bev treatment is active in elderly patients with GBM with low KPS and has an acceptable tolerance level.

Relationship between magnetic resonance imaging characteristics and plasmatic levels of MMP2 and MMP9 in patients with recurrent high-grade gliomas treated by Bevacizumab and Irinotecan

Matrix metalloproteases MMP2 and MMP9 are involved in cancer angiogenesis and invasion. We recently demonstrated that plasma MMP2 and MMP9 levels could both predict response to bevacizumab in patients with recurrent high-grade glioma (HGG). We examined the potential relationship between MMP2/MMP9 plasma levels and glioma imaging characteristics. In this retrospective, monocentric study, MRI before bevacizumab administration for HGG patients was independently analyzed for contrast enhancement (CE) and FLAIR sequences. Contemporary MMP2 and MMP9 plasma levels were assessed using ELISA kits. We analyzed 28 patients with a median Karnofsky Performance Status of 70 (range 50–80). A diffuse pattern was observed in 14 patients (50%). We did not observe any correlation between baseline imaging features and plasma levels of MMP2 or MMP9. We found no association between baseline MMP levels and diffuse MRI patterns. In univariate analyses, diffuse pattern, multi-focal disease, tumor diameter, surface area, and volume had no impact on outcome, while the number of lobes involved in CE and crossing of the midline by CE were associated with a worse progression-free survival (p = 0.072 and p = 0.012, respectively) and overall survival (p = 0.012 and p < 0.001, respectively). In patients with recurrent high-grade glioma treated with a bevacizumab-based regimen, our exploratory analysis of multiple MRI tumor characteristics at baseline failed to detect a relationship between imaging feature and plasma levels of MMP2 and MMP9. Our results suggests that number of lobes involved in CE and crossing of the midline by CE are associated with outcome although the potential prognostic versus predictive role of these markers warrant further investigation.

Thalamic laminar necrosis

We present two cases, one after status epilepticus and one after brain radiation therapy, with bilateral hyperintense thalamic lesions on T1-weighted imaging. The first patient (54-year-old woman) presented with a generalized status epilepticus following diffuse hemispheric subarachnoid hemorrhage. Initial brain MRI showed multifocal hyperintense cerebral cortex and thalami on FLAIR and DWI sequences (probably related to status epilepticus), in absence of T1-weighted signal changes. After successful antiepileptic treatment, MRI, 24 days later, showed near normalization of FLAIR/DWI abnormalities, but now showed hyperintense thalami and rightsided parietal cortex (Fig. 1). MRI, 5 months later, continued to show stable T1-weighted abnormalities. The second patient (37-year-old woman) with a history of cerebellar astrocytoma was (WHO grade III) treated at age 18 by complete surgical resection and large-field radiation therapy (including the occipital lobes and both thalami). Her clinical and radiological state (follow-up was performed with low field MRI scans) was stable for many years. There was no history of status epilepticus. A follow-up MRI, this time with a high-field 3T MRI scan at age 33, showed hyperintense occipital cortex and thalami on T1-weighted imaging (Fig. 1), still in the absence of tumor recurrence. 3T MRI, 4 years later, was stable.