Long-term impact of temozolomide on 1p/19q-codeleted low-grade glioma growth kinetics.

Although upfront temozolomide (TMZ) has been widely-used to treat 1p/19q-codeleted diffuse low-grade gliomas (LGG), its long-term impact on the growth kinetics of these tumors has not been determined. Based on serial magnetic resonance images we retrospectively evaluated the evolution of the mean tumor diameter (MTD) in 36 progressive 1p/19q-codeleted LGG treated with upfront TMZ. After TMZ onset, all but two patients (94.4%) presented a progressive MTD decrease that lasted for a median duration of 23 months (range 3-114). In 10 patients (27%) MTD regrowth occurred during TMZ treatment and in 22 patients (66%) after TMZ discontinuation. In these patients, median time to MTD regrowth after TMZ discontinuation was 12 months (range 1-88). The rate of MTD regrowth at 3 and 5 years after TMZ onset was 77 and 94%, respectively. Time to tumor progression (TTP) based on volumetric analysis was shorter than TTP based on Response Assessment in Neuro-Oncology (RANO) bidimensional criteria (23 vs. 35 months, p = 0.05) and shorter than time to next oncological treatment (23 vs. 46 months, p = 0.001). In 10 patients (27%), absence of volumetric analysis led to continue TMZ for a median of 10 cycles after MTD had started to regrow. Volumetric analysis is important to precisely assess chemotherapy efficacy in 1p/19q-codeleted LGG, identify early tumor progression and avoid futile chemotherapy continuation. In the present series, although some long-lasting volumetric responses were observed, most tumors resumed their growth within 3 years after TMZ onset.

Ongoing and prolonged response in adult low-grade gliomas treated with radiotherapy.

The aim of the present study was to evaluate the impact of first-line radiotherapy on low-grade gliomas (LGGs) growth kinetics. The mean tumor diameter (MTD) of 39 LGGs was retrospectively measured on serial magnetic resonance images before (n = 16) and after radiotherapy onset (n = 39). After radiotherapy, a decrease of the MTD was observed in 37 patients. Median duration of the MTD decrease was 1.9 years (range 0-8.1 years). According to RANO criteria, the rates of partial and minor responses were 15 and 28 % at the first evaluation after radiotherapy and 36 and 34 % at the time of maximal MTD decrease. The presence of a 1p19q codeletion and the absence of p53 expression were associated with longer durations of MTD decrease (5.3 vs 1 years, p = 0.02 and 2.4 vs 1.8 years, p = 0.05, respectively) while no association was observed between IDH1-R132H expression and duration of MTD decrease. In most patients, MTD decrease after radiotherapy occurred in two phases: an initial phase of rapid MTD decrease followed by a second phase of slower MTD decrease. Patients with a high rate of MTD decrease during the initial phase (>7 mm/year) had both a shorter duration of response (1.9 vs 5.3 years, p = 0.003) and a shorter overall survival (5.5 vs 11.6 years, p = 0.0004). LGGs commonly display a prolonged and ongoing volume decrease after radiotherapy. However, patients who respond rapidly should be carefully monitored because they are at a higher risk of rapid progression.

[Multiple gliomas: clinical studies and pathophysiological hypothesis]. / Les gliomes multiples: étude clinique et hypothèses physiopathologiques.

INTRODUCTION: Although a rare entity, multiple gliomas must be recognized and distinguished from other causes of multiple brain lesions. METHODS: Clinical and radiological features of 33 multiple gliomas were reviewed, including 20 synchronous cases and 13 metachronous cases. RESULTS: In 17 patients, radiological features were highly suggestive of spread from a primary site (multifocal gliomas). No apparent dissemination route was identified in the other cases which were presumed to be multicentric gliomas. For nine patients (27 percent), a second neoplasia or cancer was found in first degree relatives suggesting a genetic predisposition. Overall median survival was 79 weeks (64 weeks for glioblastomas). The age at onset was the main prognostic factor. CONCLUSION: Multiple gliomas represent a heterogeneous entity, probably corresponding to different mechanisms. In our group, survival was comparable to unique glioma.

Prediction of Response to Temozolomide in Low-Grade Glioma Patients Based on Tumor Size Dynamics and Genetic Characteristics.

Both molecular profiling of tumors and longitudinal tumor size data modeling are relevant strategies to predict cancer patients' response to treatment. Herein we propose a model of tumor growth inhibition integrating a tumor's genetic characteristics (p53 mutation and 1p/19q codeletion) that successfully describes the time course of tumor size in patients with low-grade gliomas treated with first-line temozolomide chemotherapy. The model captures potential tumor progression under chemotherapy by accounting for the emergence of tissue resistance to treatment following prolonged exposure to temozolomide. Using information on individual tumors' genetic characteristics, in addition to early tumor size measurements, the model was able to predict the duration and magnitude of response, especially in those patients in whom repeated assessment of tumor response was obtained during the first 3 months of treatment. Combining longitudinal tumor size quantitative modeling with a tumor''s genetic characterization appears as a promising strategy to personalize treatments in patients with low-grade gliomas.

IDH1 or IDH2 mutations predict longer survival and response to temozolomide in low-grade gliomas.

OBJECTIVES: Recent studies have shown that IDH1 and IDH2 mutations occur frequently in gliomas, including low-grade gliomas. However, their impact on the prognosis and chemosensitivity of low-grade gliomas remains unclear. METHODS: Search for IDH1 and IDH2 mutations, loss of heterozygosity on chromosomes 1p and 19q, MGMT promoter methylation, and p53 expression was performed in a series of 271 low-grade gliomas and correlated with overall survival. A subgroup of 84 patients treated up-front with temozolomide was individualized. Response to temozolomide was evaluated by progression-free survival, as well as by tumor size on successive MRI scans, and then correlated with molecular alterations. RESULTS: IDH (IDH1 or IDH2) mutations were found in 132/189 patients (70%). IDH mutation and 1p-19q codeletion were associated with prolonged overall survival in univariate (p = 0.002 and p = 0.0001) and multivariate analysis (p = 0.003 and p = 0.004). 1p-19q codeletion, MGMT promoter methylation, and IDH mutation (p = 0.01) were correlated with a higher rate of response to temozolomide. Further analysis of the course of the disease prior to any treatment except for surgery (untreated subgroup) showed that 1p-19q codeletion was associated with prolonged progression-free survival in univariate analysis, whereas IDH mutation was not. CONCLUSION: IDH mutation appears to be a significant marker of positive prognosis and chemosensitivity in low-grade gliomas, independently of 1p-19q codeletion, whereas its impact on the course of untreated tumors seems to be limited.

Gray matter involvement predicts chemosensitivity and prognosis in gliomatosis cerebri.

BACKGROUND: In gliomatosis cerebri (GC), defined as a diffuse neoplastic glial cell infiltration of the brain, upfront chemotherapy is often proposed as an alternative to radiotherapy. GC invades both white matter and gray matter in varying proportions, as reflected by the gray matter index (GMI), i.e., the estimated percentage of gray matter involvement. METHODS: The GMI was estimated in 71 patients with GC (42 men and 29 women; median age, 47 years) treated with upfront chemotherapy (7 PCV, 64 temozolomide). RESULTS: Median GMI was 30%. Patients were separated into 2 groups according to this median GMI. Compared to the 33 patients with GMI >30% (group B), the 38 patients from group A (defined as GMI

Supratentorial low-grade gliomas in older patients.

BACKGROUND: Low-grade gliomas (LGG) are thought to be very rare in elderly patients (>60 years) and have not been thoroughly studied. METHODS: A series of 62 elderly (>or=60 years of age) LGG patients were identified in a department database collecting information on pathologically identified adult supratentorial LGG. The clinical, radiologic, pathologic, and therapeutic data of these patients were analyzed and compared to those of 704 younger LGG patients (<60 years). RESULTS: Comparisons between older and younger groups showed that elderly patients more often presented with a clinical deficit (p < 0.0001), a lower Karnofsky performance status (p = 0.0002), a larger tumor on MRI (p = 0.03), and a lower rate of tumor resection (p < 0.0001). Chemotherapy was more often used as first line treatment (p = 0.001). Among the patients who died of progressive disease, 55% of the elderly patients had not received radiotherapy compared to 11% in the younger group (p < 0.0001). Survival was shorter in older patients (p < 0.0001), with a 5-year survival rate of 40%. An astrocytic phenotype (p = 0.0097), increasing age (p = 0.0049), and a tumor crossing the midline (p = 0.028) were negative prognostic factors in the older group. CONCLUSION: We found that 8% of low-grade gliomas (LGG) occur in older patients (>or=60 years of age). The clinical-radiologic picture of LGG in the elderly population differs from younger patients. Although long-term survival occurs, the course is generally more severe because elderly patients accumulate negative prognostic factors and because they are probably undertreated.

Genetic markers predictive of chemosensitivity and outcome in gliomatosis cerebri.

BACKGROUND: Up-front temozolomide (TMZ) has been recently proposed as a treatment for gliomatosis cerebri (GC), but no predictive or prognostic markers have been identified so far. Because 1p19q codeletion and methylguanine methyl transferase promoter (MGMTP) methylation have been correlated with chemosensitivity of gliomas, their value was investigated in a cohort of patients with GC treated with TMZ. METHODS: A cohort of 25 GC patients who were treated with TMZ was investigated for 1p19q codeletion and O6-methylguanine DNA. RESULTS: Patients with a 1p/19q codeletion had a higher response rate (88% [8/9] vs 25% [4/16], p = 0.002), higher progression-free survival (24.5 vs 13.7 months, p = 0.017), and higher overall survival (66.8 vs 15.2 months, p = 0.011) than patients without 1p/19q codeletion. Fourteen of 19 evaluable tumors for MGMTP status were methylated. MGMTP methylation was associated with 1p/19q codeletion (p = 0.045). Patients with unmethylated MGMTP tended to have a shorter progression-free survival and a higher rate of progressive disease. CONCLUSION: Response rate to temozolomide and prognosis seem tightly correlated to 1p19q loss. The impact of methylguanine methyl transferase promoter methylation status on gliomatosis cerebri is still unsettled in this population.

Temozolomide for low-grade gliomas: predictive impact of 1p/19q loss on response and outcome.

OBJECTIVE: To evaluate the predictive impact of chromosome 1p/19q deletions on the response and outcome of progressive low-grade gliomas (LGG) treated with up-front temozolomide (TMZ) chemotherapy. METHODS: Adult patients with measurable, progressive LGG (WHO grade II) treated with TMZ delivered at the conventional schedule (200 mg/m(2)/day for 5 consecutive days, repeated every 28 days) were retrospectively evaluated for response by central review of MRI-s. Chromosome 1p and 19q deletions were detected by the loss of the heterozygosity technique (LOH). RESULTS: A total of 149 consecutive patients were included in this retrospective, single center observational study. The median number of TMZ cycles delivered was 14 (range 2 to 30). Seventy-seven patients (53%) experienced an objective response (including 22 [15%] cases of partial response and 55 [38%] cases of minor response), 55 (37%) patients had stable disease, and 14 (10%) had a progressive disease. The median time to maximum tumor response was 12 months (range 3 to 30 months). The median progression-free survival (PFS) was 28 months (95% CI: 23.4 to 32.6). Material for genotyping was available for 86 patients. Combined 1p/19q LOH was present in 42% of the cases and was significantly associated with a higher rate (p = 0.02) and longer objective response to chemotherapy (p = 0.017), and both longer PFS (p = 4.10(-5)) and overall survival (p = 0.04). CONCLUSION: Low-grade gliomas respond to temozolomide and loss of chromosome 1p/19q predicts both a durable chemosensitivity and a favorable outcome.

Polymorphism in Sp1 recognition site of the EGF receptor gene promoter and risk of glioblastoma.

We investigated two polymorphisms of the epidermal growth factor receptor promoter as potential risk factors and prognostic markers for glioblastoma. The -216T allele (which results in a 30% higher activity) was more frequent in the patients compared with the control population (224/376 = 59.6% vs 165/352 = 46.8%; p = 0.0006) corresponding to an odd ratio of 1.67 (1.24; 2.25). A modest difference in median survival was also associated with the TT genotype.