Joint NCCTG and NABTC prognostic factors analysis for high-grade recurrent glioma

The purpose of this study is to determine prognostic factors in patients with high-grade recurrent glioma for 3 outcome variables (overall survival, progression-free survival [PFS], and PFS rate 6 months after study registration [PFS6]). Data from 15 North Central Cancer Treatment Group (NCCTG) trials (n = 469, 1980–2004) and 12 North American Brain Tumor Consortium (NABTC) trials (n = 596, 1998–2002) were included. Eighteen prognostic variables were considered including type of treatment center (community/academic) and initial low-grade histology (yes/no). Recursive partitioning analysis (RPA), Cox proportional hazards, and logistic regression models with bootstrap resampling were used to identify prognostic variables. Longer survival was associated with last known grade (Grade) of III, younger age, ECOG performance score (PS) of 0, shorter time from initial diagnosis (DxTime), and no baseline steroid use. Factors associated with longer PFS were Grade III and shorter DxTime. For patients without temozolomide as part of the treatment regimen, the only factor associated with better PFS6 was Grade III, although DxTime was important in RPA and PS was important in logistic regression. Grade was the most important prognostic factor for all three endpoints regardless of the statistical method used. Other important variables for one or more endpoints included age, PS, and DxTime. Neither type of treatment center nor initial low-grade histology was identified as a major predictor for any endpoint.     

贝伐单抗治疗高级别脑胶质瘤的研究进展

脑胶质瘤中3/4以上的患者为高级别脑胶质瘤,其恶性程度高,术后易复发,预后极差。虽然术后同步放化疗能使高级别脑胶质瘤患者生存获益,但其仅能延长有限的生存时间。近年来,肿瘤的分子靶向治疗逐渐成为研究热点。血管内皮生长因子在脑胶质瘤及其周围组织中高表达,调控着肿瘤的生长过程,是脑胶质瘤治疗的有效靶点。贝伐单抗能够特异性地阻止血管内皮生长因子与其受体结合,抑制肿瘤血管的形成;同时还能使肿瘤血管正常化,改善血管通透性,增加肿瘤组织有效药物浓度,从而达到其抗肿瘤的作用。本文就贝伐单抗的作用机制及近些年贝伐单抗单药与联合化疗或其他药物治疗高级别脑胶质瘤的研究进展进行综述。      

Occupational risk factors for low grade and high grade glioma: results from an international case control study of adult brain tumours

The majority of suspected occupational risk factors for adult brain tumours have yet to be confirmed as etiologically relevant. Within an international case-control study on brain tumours, lifelong occupational histories and information on exposures to specific substances were obtained by direct interviews to further investigate occupational risk factors for glioma. This is one of the largest studies of brain tumours in adults, including 1,178 cases and 1987 population controls from 8 collaborating study centres matched for age, gender and centre. All occupational information, was aggregated into 16 occupational categories. In a pooled analysis, odds ratios (OR), adjusted for education, were estimated separately for men and women and for high-grade glioma (HGG) and low-grade glioma (LGG), focusing especially on 6 categories defined a priori: agricultural, chemical, construction, metal, electrical/electronic and transport. For men, an elevated OR of glioma associated with the category "metal" (OR = 1.24, 95% CI 0.96-1.62) was seen, which appeared to be largely accounted for by LGG (OR = 1.59, 95% CI 1.00-2.52). For the other 5 occupational categories, no elevated risks for glioma were observed. For women the only noteworthy observation for the 6 a priori categories was an inverse association with the "agriculture" category (OR = 0.60, 95% CI 0.36-0.99). Apart from the 6 major categories, women working in food production or food processing (category "food") showed an increased OR of 1.95 (95% CI 1.04-3.68). None of the 20 substance groups was positively associated with glioma risk. Although some other point estimates were elevated, they lacked statistical significance. The results do not provide evidence of a strong association between occupational exposures and glioma development.     

高分级脑胶质瘤术后同步放化疗联合辅助化疗的临床研究

目的:探讨高分级脑胶质瘤术后同步放化疗联合辅助化疗的临床效果。方法:选取高分级脑胶质瘤手术患者138例,随机分为两组,使其具有可比性。对照组67例,给予单纯放射治疗。观察组71例,在对照组基础上给予同步化疗和辅助化疗。对两组患者治疗效果进行统计。随访三年,记录三年期间生存率。结果:观察组患者完全缓解、部分缓解、稳定、进展和有效率分别为47.89%、40.85%、8.45%、2.82%和88.73%,对照组分别为28.36%、32.84%、13.43%、25.37%和61.19%,观察组患者完全缓解率和有效率均明显高于对照组,两组比较差异有统计学意义（P<0.05）。观察组患者术后一年、两年、三年生存率分别为91.55%、69.01%和50.70%,对照组分别为50.75%、16.42%和10.45%,观察组明显高于对照组,两组比较差异有统计学意义（P<0.05）。观察组患者发生恶心呕吐、中性粒细胞下降以及血小板减少者分别占63.38%、49.30%和52.11%,对照组分别为62.69%、46.27%和52.24%,两组比较差异无统计学意义。结论:高分级脑胶质瘤患者在术后进行同步放化疗联合辅助化疗可以有效提高患者的治疗效果,改善患者预后,不会增加不良反应,因此是一种安全而有效的治疗方案。     

高级别胶质瘤手术联合术后辅助放化疗的疗效分析（附56例）

目的:探讨高级别胶质瘤的手术和术后放化疗的治疗效果。方法:回顾性分析56例高级别胶质瘤患者的临床资料,均采用手术、术后同步放化疗及6个周期以上的替莫唑胺化疗,对其治疗效果和不良反应进行评价分析。结果:56例患者手术全切除10例（17.9%）,次全切除35例（62.5%）,部分切除11例（19.6%）。分子病理提示IDH1132H突变19例;MGMT基因启动子甲基化20例。随访过程中13例未见明显复发;35例复发;1例出现脊髓的多发转移灶;7例出现放射性脑损伤,其中3例再次手术减压,4例保守治疗。12个月、24个月和36个月总生存率分别为66.1%、50.0%和32.1%;无进展生存率分别为57.1%、39.3%和25.0%。结论:高级别胶质瘤预后不佳,术后残留、复发、转移和放射性损伤是治疗的重点和难点;MGMT基因启动子甲基化患者总体生存率和无进展生存率高于MGMT启动子未甲基化患者。     

Treatment of recurrent malignant glioma with BCNU-fluosol and oxygen inhalation. A phase I-II study

Objectives: To evaluate the toxicity and response rate following BCNU with oxygen inhalation and escalatingdosages of fluosol administered to patients with radiographic progression of malignant glioma after definitivesurgery and radiotherapy. Method: This single arm, phase I-II multicenter trial, enrolled 99 patients withmalignant gliomas recurrent after definitive surgery and radiotherapy. All patients received a fixed dose(200 mg/m²) of BCNU along with 100% oxygen and fluosol, a perfluorochemical. Fluosol doses were escalat-edbetween patients (150, 275, 400 and 600 ml/m²). Treatment was repeated every 6 weeks for a maximum of 6cycles. Patients were assessed for toxicity at the time of infusion and sequentially thereafter. Response wasevaluated clinically and radiologically at least every 6 weeks. Results: Treatment was well tolerated. Dosereductions were required at least once in 18 patients, treatment delays were necessary at least once in 33patients. Grade 3-4 leukopenia occurred in 6 patients (12 events), grade 3-4 thrombocytopenia in 10 patients(25 events) and grade 3-4 liver enzymes elevations in 18 patients (31 events). Higher fluosol dosages did notproduce increases in toxicity or responses. Response or stabilization was seen in 57% (38% were stabiliza-tions)of the patients who entered the trial with progressive disease. The median time to progression was 45weeks, and median survival was 66 weeks for patients who had response or stabilization. For patients withglioblastoma response/stabilization was seen in 45% with a mean duration of 24 weeks, for patients withanaplastic astrocytoma response/stabilization was seen in 68% with a mean duration of 50 weeks. Conclusion:This treatment regimen is well tolerated. Our results suggest fluosol may enhance the effectiveness of BCNUfor the treatment of recurrent malignant gliomas. Future studies will be performed using fluosol at the dose of400 ml/m².     

Occupational exposure to low frequency magnetic fields and the risk of low grade and high grade glioma

Objective The purpose of this population-based case control study was to investigate a possible association between occupational exposure to low frequency magnetic fields and the risk of low grade glioma (LGG) and high grade glioma (HGG). Methods The study population consisted of 414 histologically confirmed cases of glioma (LGG = 110, HGG = 304), first diagnosed between July 1987 and December 1991, and 421 controls from Melbourne, Australia, matched by age, sex and postcode of residence. A detailed occupational history was obtained for each subject. Exposure to low frequency magnetic fields was estimated using three different methods: self-report, expert hygienist review and a job exposure matrix (JEM). Results Elevated but statistically non-significant risk estimates were found for all glioma and HGG when exposure was assessed by the expert hygienist. The odds ratios (OR) for the highest exposed group of workers when assessed by the expert hygienist were 1.4 (95% confidence interval, CI: 0.85–2.27) and 1.51 (95% CI: 0.90–2.53) for all glioma and HGG, respectively. There were inverse associations for the self-reported and JEM exposures for both LGG and HGG but these may reflect limitations in these exposure assessment methods. Conclusions Our results do not support a role for occupational exposure to low frequency magnetic fields in the development of either LGG or HGG. This work was performed at the Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia     

Nimotuzumab in combination with radiotherapy in high grade glioma patients: A single institution experience

Nimotuzumab, a humanized antibody targeting epidermal growth factor receptor, has potent anti-proliferative, anti-angiogenic, and pro-apoptotic effects in vitro and in vivo. It also reduces the number of radio-resistant CD133⁺ glioma stem cells. The antibody has been extensively evaluated in patients with advanced head and neck, glioma, lung, esophageal, pancreatic, and gastric cancer. In this single institution experience, 35 patients with anaplastic astrocytoma (AA) or glioblastoma multiforme (GBM) were treated with irradiation and 200 mg doses of nimotuzumab. The first 6 doses were administered weekly, together with radiotherapy, and then treatment continued every 21 days until 1 year. The median number of doses was 12, and the median cumulative dose was thus 2400 mg of nimotuzumab. The most frequent treatment-related toxicities were increase in liver function tests, fever, nausea, anorexia, asthenia, dizziness, and tremors. These adverse reactions were classified as mild and moderate. The median survival time was 12.4 mo or 27.0 mo for patients with GBM or AA patients, respectively, who received curative-intent radiotherapy in combination with the antibody. The survival time of a matched population treated at the same hospital with irradiation alone was decreased (median 8.0 and 12.2 mo for GBM and AA patients, respectively) compared with that of the patients who received nimotuzumab and curative-intent radiotherapy. We have thus confirmed that nimotuzumab is a very well-tolerated drug, lacking cumulative toxicity after maintenance doses. This study, in a poor prognosis population, validates the previous data of survival gain after combining nimotuzumab and radiotherapy, in newly diagnosed high-grade glioma patients.     

Osmotic blood-brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review

Summary In the past, chemotherapeutic treatment of patients with high grade malignant gliomas following surgery and radiation has not added significantly to the 12–14 month median survival rate. Over four years, 37 patients with high grade malignant gliomas underwent 246 treatment procedures with a combination of methotrexate, cyclophosphamide, and procarbazine given in association with hyperosmolar mannitol-induced transient breakdown of the blood-brain barrier. These patients have demonstrated a median survivorship of 22 months after considering age, Karnofsky Performance Score, and necrosis by the Cox Proportional Hazards model. The study group had a mean age of 43 years, and mean Karnofsky Performance Score of 67%. Sixty-five percent of the procedures had well-documented barrier disruption. Sixteen percent remained in complete remission while 24 patients (65%) had partial or temporary remission. Progression-free intervals after blood-brain barrier disruption/chemotherapy ranged from 1–47 (mean 15) months. Neurotoxicity has been minimal with one peri-procedural mortality and five patients suffering an increase in neurologic deficit after a procedure. The results of this study are consistent with and further extend the reported literature on this method of brain tumor therapy as described in other centers. Chemotherapy in conjunction with osmotic disruption of the blood-brain barrier may provide the pharmacokinetic advantage sufficient to significantly improve survival in patients with high grade malignant glioma.     

高分级脑胶质瘤术后精确放疗患者的预后影响因素

目的:分析高分级脑胶质瘤术后精确放疗患者预后的危险因素及干预对策。方法:回顾自2009年6月至2013年6月入我院的病理诊断为高分级脑胶质瘤术后精确放疗的患者资料。对患者的一般情况如性别、年龄、手术切除程度、病理分级、化疗、放疗量、KPS评分、术前癫痫发作、总生存期（随访2年）等数据进行分析,评价高分级脑胶质瘤术后精确放疗患者预后的危险因素。结果:在123例患者中,年龄16~86岁,平均发病年龄46.9岁,男性平均发病年龄42.0岁,女性平均发病年龄49.5岁。小于40岁患者68例,大于等于40岁患者55例。从发病到明确诊断平均时间9.8月,中位生存时间19个月,1年生存率69%,2年生存率37.4%。单因素分析显示,年龄、手术切除程度、病理分级、化疗与高分级脑胶质瘤术后精确放疗患者预后显著相关（P＜0.05）,性别、放疗、术前癫痫发作、KPS评分与高分级脑胶质瘤术后精确放疗患者预后无明显相关（P>0.05）。多因素COX回归分析显示,年龄<40岁（RR=1.844,95%CI:1.047~3.249）、肿瘤全切（RR=2.348,95%CI:1.389~3.968）、病理分级3级（RR=2.632,95%CI:1.479~4.684）、同步替莫唑胺化疗（RR=0.557,95%CI:0.329~0.944）能够显著延长患者的总生存时间。结论:年龄、手术切除程度、病理分级、化疗等是高分级脑胶质瘤术后精确放疗患者生存预后的危险因素。年龄<40岁、肿瘤全切、病理分级低、同步化疗患者生存预后较好。     

Delay in radiotherapy shortens survival in patients with high grade glioma

Fractionated external beam radiotherapy is an important component of standard treatment for high grade glioma. Due to resource constraints, patients may experience delays in receiving treatment. The purpose of this study was to evaluate the effect of radiotherapy waiting time on survival in patients with high grade glioma. A retrospective analysis was performed of 172 patients with a histological diagnosis of WHO Grade 3 or 4 Astrocytoma who had undergone surgery at Wellington Hospital between 1993 and 2003, and who subsequently underwent radiotherapy. Time to radiotherapy after surgery varied from 7 days to over 16 weeks. Multiple Cox regression analysis showed that age, performance status, tumour grade, extent of surgical resection, radiotherapy dose, and time to radiotherapy from day of surgery were all independently related to survival. Every additional week of delay until the start of radiotherapy increases the risk of death (hazard ratio) by 8.9% (95%CI 2.0%–16.1%). A 6 week delay in starting radiotherapy (from 2 weeks post-op to 8 weeks) reduces median survival by 11 weeks for a typical patient. Delay in radiotherapy results in a clinically significant reduction in survival. These findings have implications for resource allocation and for the design of clinical trials. This study was approved by the Central Regional Ethics Committee, New Zealand.     

Changing boundaries in the treatment of malignant gliomas

Malignant gliomas are still among the most lethal and difficult tumors to treat; even the most intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on survival for most of these patients, as long-term survivors are less than 10%. There is a major need for new chemotherapeutic drugs and alternative therapeutic modalities. This review aims to define the best standard treatment in the common clinical practice and also summarizes the most promising lines of investigational research in the field of neuro-oncology, which will probably offer new and long-awaited valid therapy options for brain tumor patients.     

Investigation on the role of integrated PET/MRI for target volume definition and radiotherapy planning in patients with high grade glioma

Purpose

To evaluate the impact of fluid-attenuated-inversion-recovery MRI (FLAIR/MRI) and Carbon-11-labeled-methionine PET (11C-MET-PET) on high grade glioma (HGG) tumor volume delineation for radiotherapy planning.

Material and methods

Sixty-nine patients with HGG were evaluated. The clinical target volumes (CTV1, generated by adding a 10 mm margin to FLAIRMRI area, CTV2 by adding a 20 mm margin to enhanced T1MRI) and biological target volume (BTV) were delineated on pre-operative MRI images and 11CMETPET respectively.

Results

The overlap between CTV1 and CTV2 showed a low correlation between the two volumes with CTV1 not always fully included into the CTV2. In all cases the whole BTV was included into the CTV1, while in 35/69 patients (50%) part of BTV was outside the CTV2 despite larger margins were added. In all cases recurrences were within the CTV1 volume and in 19/38 (50%) partially outside the CTV2. In all patients relapse corresponded to the BTV area.

Conclusions

Our data suggest that the target volume definition using FLAIR–MRI is more adequate compared to enhanced T1MRI. 11C-METPET uptake could help identify microscopic residual areas.     

Early vs. delayed radiotherapy in a small cohort of patients with supratentorial low grade glioma

In a cohort of 25 patients with supratentorial low grade glioma, the timing of radiotherapy made no significance difference for 10 year survival. Patients who received early radiotherapy had a 55% 10 year survival and those receiving delayed radiotherapy had a 53% 10 year survival. Radiotherapy was delayed a median of 4.8 years in those receiving delayed radiotherapy.     

低级别胶质瘤复发、恶变中VEGF、EGFR表达的变化及意义

目的 低级别胶质瘤预后的决定因素很多,但即使是相同情况下预后也可以明显不同。部分低级别胶质瘤术后很快复发,且伴有病理级别的升高,这部分病人的预后较差。本研究旨在探讨在低级别胶质瘤复发恶变中VEGF和EGFR表达的变化,并分析这些变化的意义。方法 采用免疫组化SP二步法对24对初发低级别及复发、恶变后高级别胶质瘤标本分别进行VEGF和EGFR的表达检测,分析它们在低级别胶质瘤初发和复发、恶变过程中的表达差异。结果 与初发的低级别胶质瘤标本相比,VEGF、EGFR在复发、恶变后的表达率明显升高,其表达差异有统计学意义(P＜0.05)。结论 本研究表明VEGF和EGFR在低级别胶质瘤复发、恶变中起到非常重要的作用。VEGF和EGFR的表达可以作为低级别胶质瘤预后的指标之一,并为今后胶质瘤的靶向治疗提供理论依据。     

The use of dynamic O-(2-18F-fluoroethyl)-l-tyrosine PET in the diagnosis of patients with progressive and recurrent glioma

BackgroundWe evaluated the diagnostic value of static and dynamic O-(2-[¹⁸F]fluoroethyl)-l-tyrosine (¹⁸F-FET) PET parameters in patients with progressive or recurrent glioma.MethodsWe retrospectively analyzed 132 dynamic ¹⁸F-FET PET and conventional MRI scans of 124 glioma patients (primary World Health Organization grade II, n = 55; grade III, n = 19; grade IV, n = 50; mean age, 52 ± 14 y). Patients had been referred for PET assessment with clinical signs and/or MRI findings suggestive of tumor progression or recurrence based on Response Assessment in Neuro-Oncology criteria. Maximum and mean tumor/brain ratios of ¹⁸F-FET uptake were determined (20–40 min post-injection) as well as tracer uptake kinetics (ie, time to peak and patterns of the time–activity curves). Diagnoses were confirmed histologically (95%) or by clinical follow-up (5%). Diagnostic accuracies of PET and MR parameters for the detection of tumor progression or recurrence were evaluated by receiver operating characteristic analyses/chi-square test.ResultsTumor progression or recurrence could be diagnosed in 121 of 132 cases (92%). MRI and ¹⁸F-FET PET findings were concordant in 84% and discordant in 16%. Compared with the diagnostic accuracy of conventional MRI to diagnose tumor progression or recurrence (85%), a higher accuracy (93%) was achieved by ¹⁸F-FET PET when a mean tumor/brain ratio ≥2.0 or time to peak <45 min was present (sensitivity, 93%; specificity, 100%; accuracy, 93%; positive predictive value, 100%; P < .001).ConclusionStatic and dynamic ¹⁸F-FET PET parameters differentiate progressive or recurrent glioma from treatment-related nonneoplastic changes with higher accuracy than conventional MRI.