Phase II study of two-weekly temozolomide in patients with high-grade gliomas.

Palliative chemotherapy has an increasing role in the management of recurrent high-grade gliomas. Temozolomide is a well-tolerated agent that results in objective responses and stabilisation of disease. Theoretically, temozolomide may be more effective when given in a prolonged schedule rather than the standard 5 days-monthly schedule. This Phase II study examined the efficacy and toxicity of temozolomide when given in a two-weekly schedule. Twenty-five patients received 150 mg/m2 temozolomide daily for seven days alternating with seven days of no treatment. One cycle of temozolomide was a total of two weeks treatment in every 28 days. Of the 25 evaluable patients, there was one complete response (4%), four partial responses (16%) and 10 patients had disease stablisation (40%). The progression free survival at 6 months was 56%. Two-weekly temozolomide was well tolerated with only four episodes of Grade 3 thrombocytopenia. Overall, two-weekly temozolomide is an active and well tolerated schedule, but does not appear to improve on the activity of temozolomide using the standard 5-day schedule.     

Rechallenge with temozolomide in patients with recurrent gliomas

Temozolomide (TMZ) is the standard of care for patients with newly diagnosed glioblastoma (GBM) as well as those with recurrent anaplastic glioma (AG) and GBM. It has become common practice to re-expose patients to TMZ who had been previously treated with TMZ, or to switch patients to alternative dosing regimens of TMZ when there are signs of relapse or progress on standard TMZ therapeutic regimens. To date, however, there is a scarcity of data on the efficacy of this therapeutic strategy, currently referred to as TMZ rechallenge. We have conducted a retrospective review of patients with recurrent glioma rechallenged with TMZ. Patients experiencing progressive disease (PD) during TMZ therapy who were rechallenged with alternative TMZ regimens and patients rechallenged after stable disease in a TMZ-free interval were evaluated separately. A total of 90 rechallenges were identified in 80 patients. The progression-free survival at 6 months (PFS-6) was 48% in patients with AG (12/25) and 27.7% in those with GBM (14/47). The PFS-6 was 16.7% in AG and 26.3% in GBM for patients switched during TMZ and 57.9 and 28.6% in patients rechallenged after a TMZ-free interval of at least 8 weeks. Relevant hematological toxicity (NCI-CTC grade 3–5) was observed in 22 of 90 rechallenges, and relevant non-hematological in ten of 90 rechallenges. Temozolomide was well tolerated and generated promising PFS-6 in patients who had previously failed TMZ, regardless if they progressed during TMZ treatment, or if they were rechallenged after a TMZ-free interval. These results suggest that the TMZ rechallenge strategy warrants further investigation in a prospective randomized trial.     

Clinical study of apatinib plus temozolomide for the treatment of recurrent high-grade gliomas

ObjectivesRecurrent high-grade glioma, a malignant tumor of the brain or spinal cord associated with poor prognosis with a median survival of <6 months. Recurrent high-grade glioma does not have standard treatment even if some strategies have some effect in recurrent gliomas. Apatinib, as a tyrosine kinase inhibitor shown to be effective in treating the lung and gastric cancer. The present study investigated the efficacy and safety of apatinib in combination with dose-dense regimens of temozolomide for treating recurrent glioma.Patients and methodsEighteen patients with recurrent high-grade glioma were enrolled and treated with apatinib (500 mg/day) and TMZ (50 mg/m²/day). Patients who achieved partial response or stable disease continued treatment. Administration of drug was terminated for patients with progressive disease, who could not tolerate toxicity, and who required discontinuation due to other medical conditions.ResultsFrom the 18 cases, only 17 were included in the evaluation of the curative effect of the drug and in that four showed partial responses, ten had stable disease, remaining three exhibited progressive disease. The disease control rate was 82.3% (14/17). Progression-free and overall survival was found to be 4 months and 9.1 months, respectively. Three patients became transiently capable of self-care (Karnofsky performance status >70). Cognition and quality of life improved after treatment and from the safety perspective, three most common adverse reactions included epilepsy (24.1%), hypertension (20.7%), and fatigue (17.2%).ConclusionApatinib and TMZ may represent an alternative treatment option for patients with recurrent high-gradeglioma, especially those with a low Karnofsky performance status. However, studies using a larger sample size are required to confirm these findings.     

顺铂联合替莫唑胺治疗MGMT启动子非甲基化的 复发高级别胶质瘤

目的 探讨顺铂（DDP）联合替莫唑胺（TMZ）治疗MGMT启动子非甲基化的复发高级别胶 质瘤的疗效。方法 纳入2016 年4 月30 日至2018 年3 月31 日收治55 例MGMT启动子非甲基化的复发 高级别胶质瘤,均经过手术病理证实为高级别胶质瘤（WHO Ⅲ级或Ⅳ级）和MGMT启动子非甲基化。随 访期间经头颅MRI 和（或）再次手术的病理确诊为肿瘤复发,并给予DDP联合TMZ化疗。观察患者的不 良反应和生存情况。结果 WHO Ⅲ级有效率为12.0%（3/25）,中位生存期为42 个月;WHO Ⅳ级有效率 为6.7%（2/30）,中位生存期为17 个月。总有效率为9.1%（5/55）,总生存期为19 个月。不良反应主要为骨 髓抑制、胃肠道症状和肝肾功能损伤,经对症治疗后均恢复。结论 DDP 联合TMZ 治疗MGMT 启动子 非甲基化的复发高级别胶质瘤具有一定的疗效。     

Effects of palliative treatment with temozolomide in patients with high-grade gliomas

BACKGROUND AND PURPOSE: The aim of the study was to assess the results of treatment with temozolomide in patients with high-grade gliomas who no longer benefit from surgical treatment and radiotherapy. MATERIAL AND METHODS: The retrospective analysis included 51 patients treated between 2001 and 2007 in the Centre of Oncology in Kraków. Glioblastoma multiforme was histologically diagnosed in 24 (47%) patients; anaplastic astrocytomas and other grade III gliomas (according to WHO classification) were diagnosed in 27 (53%) patients. Patients received 1-11 cycles of treatment with temozolomide - 210 cycles were given in total. Forty-five patients were eligible for efficacy assessment because 6 patients received only one chemotherapy cycle (due to rapid progression of the glioma). RESULTS: According to the radiological assessment, 6 patients (13%) had an objective response and a further 16 patients (36%) had stabilization of the glioma. Subjective improvement was noted in 26 patients (58%), and neurological improvement was observed in 14 patients (31%). The median survival in the whole group was 41 weeks (40 weeks in patients with glioblastoma multiforme and 54 weeks in patients with anaplastic gliomas). One-year overall survival in the above-mentioned groups was 40.7%, 22%, and 50%, respectively. Two-year overall survival was 16%, 8%, and 20.9%, respectively. Adverse events were observed during 73 (35%) cycles of treatment and prompted a dose reduction in 12 (24.5%) patients. The most frequent adverse events were: thrombocytopenia, leukopenia, nausea and vomiting. Adverse events did not lead to treatment withdrawal in any patient. CONCLUSIONS: Objective benefit from the temozolomide treatment (stabilization or objective remission) was observed in 49% of patients irrespective of histological diagnosis. Tolerability of treatment with temozolomide in patients with high-grade gliomas is good.     

Prolonged survival in adult neurofibromatosis type I patients with recurrent high-grade gliomas treated with bevacizumab

Astrocytic tumors, especially optic pathway pilocytic astrocytomas, are common in pediatric NF1 patients. High-grade gliomas (HGGs) appear to be rare in adult and pediatric NF1 patients. This is a series of five consecutive, adult NF1 patients with recurrent HGGs treated at The University of Texas MD Anderson Cancer Center. Four patients met consensus clinical criteria for NF1 and one patient had presumed segmental NF1. Three patients had glioblastomas, one gliosarcoma, and one progressive, enhancing optic pathway glioma which was not biopsied. Two tumors had molecular testing performed; both were IDH wild type and activating oncogene mutations (1 BRAFV600E and 1 PIK3CA mutation) were found in these tumors. All five patients received bevacizumab-containing regimens at tumor recurrence. The median number of 4-week cycles of bevacizumab was 20. All five patients experienced prolonged post-recurrence survival following bevacizumab treatment ranging from ten to 72 months. The median overall survival from HGG diagnosis was 72.6 months with three patients alive and progression free at last follow-up. Three out of five patients developed vascular complications leading to bevacizumab discontinuation. In this case series, adult NF1 patients with recurrent HGGs had prolonged, post-recurrence survival after treatment with bevacizumab-containing regimens. Based on these results, further study of antiangiogenic therapy in NF1 patients with HGGs and bevacizumab-response in sporadic HGG patients with NF1-mutated tumors is warranted.     

Prognosis of pediatric high-grade gliomas with temozolomide treatment: a retrospective, multicenter study

Purpose

We analyzed the usefulness of initial or recurrent treatment of temozolomide (TMZ) in pediatric high-grade gliomas (HGGs).

Methods

Between 2002 and 2010, we performed surgery on 35 patients with 17 glioblastomas, 14 anaplastic astrocytomas, 3 anaplastic oligodendrogliomas, and 1 anaplastic oligoastrocytoma. The male-to-female ratio was 21:14, and the median age was 13?years (range, 3–18?years). The mean follow-up period was 15.9 (±1.8) months. As the TMZ treatment, 22 patients received the initial treatment and 13 patients at recurrence. We analyzed the prognostic significance of TMZ treatment, tumor location, extent of removal, pathology, and recurrence pattern.

Results

The median progression-free survival (PFS) and overall survival (OS) were 9.7 (±1.4) and 17.8 (±2.5) months, respectively. Based on univariate analysis, the median PFS was 9.9 (±1.6) months in the tumors located in the cerebral hemisphere and 5.6 (±1.3) months in the diencephalon (p?=?0.03). Median PFS was 12.5 (±1.7) months in the initial treatment and 6.8 (±0.8) months in the recurrent treatment (p?=?0.03). The median OS was 14.9 (±2.3) months in glioblastomas and 24.4 (±4.1) months in tumors with an anaplastic pathology (p?=?0.01). The median OS was 12.1 (±3.7) months in patients with cerebrospinal fluid (CSF) dissemination and 18.2 (±2.9) months in patients without CSF dissemination (p?=?0.02). Grades 3 and 4 treatment-related toxicity occurred in 7.7–9?% of the patients.

Conclusions

Initial or recurrent TMZ treatment in pediatric HGGs was safe and tolerable. Initial treatment showed improved PFS compared to recurrent treatment, and both showed similar OS.     

Factors predicting temozolomide induced clinically significant acute hematologic toxicity in patients with high-grade gliomas: A clinical audit

Introduction

Myelo-suppression, the dose-limiting toxicity of alkylating cytotoxic agents is generally perceived to be uncommon with temozolomide (TMZ), a novel oral second generation imidazotetrazinone prodrug, with a reported incidence of 5–10% of grade 3–4 acute hematologic toxicity. We were observing a higher incidence of clinically significant myelo-toxicity with the standard schedule of TMZ, particularly in females, prompting us to do a clinical audit in our patient population.

Methods

One hundred two adults (>18 years of age) treated with TMZ either for newly diagnosed or recurrent/progressive high-grade glioma constituted the study cohort. Clinically significant acute hematologic toxicity was defined as any one or more of the following: any grade 3–4 hematologic toxicity; omission of daily TMZ dose for ≥3 consecutive days during concurrent phase; deferral of subsequently due TMZ cycle by ≥7 days during adjuvant phase; dose reduction or permanent discontinuation of TMZ; use of growth factors, platelets or packed-cell transfusions during the course of TMZ. Uni-variate and multi-variate analysis was performed to correlate incidence of acute hematologic toxicity with baseline patient, disease, and treatment characteristics.

Results

The incidence of clinically significant neutropenia and thrombocytopenia was 7% and 12% respectively. Seven (7%) patients needed packed-cells, growth factors, and/or platelet transfusions. Grade 3–4 lymphopenia though common (32%) was self-limiting and largely asymptomatic. Two (2%) patients, both women succumbed to community acquired pneumonia during adjuvant TMZ. Multi-variate logistic regression analysis identified female gender, grade IV histology, baseline total leukocyte count <7700/mm³ and baseline serum creatinine ≥1 mg/dl as factors associated with significantly increased risk of clinically significant acute hematologic toxicity.

Conclusion

The incidence of TMZ induced clinically significant neutropenia and thrombocytopenia was low in our patient population. Severe lymphopenia though high was largely asymptomatic and self-limiting. Gender, grade, leukocyte count, and serum creatinine were significant independent predictors of severe acute myelo-toxicity.     

应用替莫唑胺对照司莫司丁治疗恶性脑胶质瘤的疗效观察

目的应用替莫唑胺（TMZ）以司莫司丁（CCNU）作为对照研究两者对恶性脑胶质瘤化疗的有效性.方法一年内入组合格患者55例,随机分成两组,按体表面积分别给以两种药物化疗并每月进行临床随访、定期复查头颅强化CT或MRI与化疗前资料比较判断病情变化.结果影像所示肿瘤实体的缓解率TMZ组为44.74%,CCNU组为11.77%,P=0.017.临床功能改善率TMZ组为53%,CCNU组为12%,P=0.017.结论TMZ比CCNU有较高的缓解率,更好的改善临床功能,可有效的提高生活质量.希望更长期更广泛的研究验证和改进本试验.     

Safety and feasibility of long-term temozolomide treatment in patients with high-grade glioma

We surveyed neuro-oncologists regarding patients treated with temozolomide for at least 12 cycles or 12 months. Patients receiving first-line temozolomide for a median 13 cycles had a median progression-free survival (PFS) of 14 months. Patients with recurrent disease receiving a median 14 cycles had a median PFS of 15.5 months. A small percentage of patients experienced grade III to IV toxicity. These results suggest that long-term treatment with temozolomide is feasible and well tolerated.     

MRI in patients with high-grade gliomas treated with bevacizumab and chemotherapy

Patients with recurrent gliomas (n = 14) were treated with bevacizumab and carboplatin, cpt-11, or etoposide. Follow-up MRI scans were obtained 2 to 6 weeks after initiation of treatment. Contrast-enhancing tumor shrank in 7 patients, with reductions evident in as little as 2 weeks after initiation of therapy. Treatment seemed more effective for heterogeneously enhancing tumor compared with solidly enhancing tumor.     

替莫唑胺胶囊治疗恶性脑胶质瘤30例疗效分析

目的评价替莫唑胺胶囊（TMZ）治疗人脑恶性胶质瘤的临床疗效及不良反应。方法2005年1月至2008年1月对一个单位30例术后确诊的恶性脑胶质瘤且使用TMZ化疗的患者进行随访,观察近期治疗反应、生存期,并分析常规病理和分子病理对治疗效果的影响。结果TMZ治疗结束时,30例患者客观有效率和疾病控制率分别为53．3％和80．0％,O^6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）对近期疗效无明显影响（P〉0．05）,而不同病理类型的近期疗效存在明显差异（P〈0．05）。随访期间共有12例患者死亡,生存期为0．7～3．7年,中位生存期为1．5年。MGMT阳性和阴性患者的中位生存期分别为1．3年和1．5年,无明显差异（P：0．31）。胶质母细胞瘤和间变型星形细胞瘤的中位生存期分别为1．3年和2．0年,亦无明显差异（P=0．28）。不良反应包括厌食、便秘等消化道症状11例（36．7％）,白细胞减少3例（10．0％）,假性进展2例（6．7％）。结论TMZ对恶性胶质瘤患者有较好的临床疗效,不良反应少,耐受性好,治疗方案简便,是一种理想的恶性胶质瘤术后辅助化疗药物。     

Radiation induced early necrosis in patients with malignant gliomas receiving temozolomide

Background

Temozolomide is the major drug in the treatment of malignant gliomas. Radiation induced necrosis can behave radiologically and clinically like a recurrent tumor. The major problem is the differentiation between recurrence and radiation injury especially in early phases of treatment. The aim of this study was to evaluate the patients receiving temozolomide showing early clinical or radiological progression and impact of early necrosis on follow-up.

Patients and methods

We retrospectively evaluated medical records of 67 patients with malignant glioma receiving temozolomide. All patients received concomitant radiotherapy and temozolomide followed by adjuvant temozolomide. In case of any radiological or clinical progression, MRI spectroscopy evaluation was used to confirm tumoral progression.

Results

Radiological or clinical progression was observed in 17 (25.4%) patients. Early radiation induced necrosis was diagnosed in 4 of 17 patients (23.5%) by surgery (n = 3) and MRI spectroscopy (n = 1). The observed incidence of pseudoprogression was 4 in 67 (6%) patients. Patients with diagnosis of early radiation injury had median progression-free survival of 7 months compared to 5 months in patients without radiation damage (p = 0.004). However, there was no statistically significant difference in terms of overall survival between groups.

Conclusion

Temozolomide can cause early radiation induced injury which can mimic progressive tumor. Although the discrimination between two entities results in the accurate evaluation of response to therapy and benefits those patients, it did not affect overall survival. MRI spectroscopy is a valuable tool to define early radiation necrosis and should be further evaluated in larger prospective studies.     

Pilot study of the combination of EGFR and mTOR inhibitors in recurrent malignant gliomas

Malignant gliomas are frequently characterized by amplification of the epidermal growth factor receptor (EGFR) and loss of PTEN tumor suppressor gene. Twenty-eight heavily pretreated patients with recurrent malignant gliomas were administered EGFR inhibitors (gefitinib or erlotinib) in combination with the mTOR (mammalian target of rapamycin) inhibitor sirolimus. The regimens were reasonably well tolerated. Nineteen percent of patients experienced a partial response and 50% had stable disease. Six-month progression-free survival for glioblastoma patients was 25%.     

An Australian experience with temozolomide for the treatment of recurrent high grade gliomas.

Temozolomide has an evolving role in the treatment of high grade gliomas. Recent studies suggest that temozolomide is well tolerated and efficacious. This study retrospectively analysed the activity and toxicity associated with temozolomide at two Australian centres over a 24 month period. Fifty-six patients with recurrent high grade gliomas were treated with temozolomide. Patients received temozolomide orally at 150-200mg/m(2)daily, days 1-5, every 4 weeks. The median number of treatment cycles was 4 (1-12). Of the 56 patients, 15 (27%) achieved complete or partial response and 18 (32%) achieved minor response or stable disease. There were no episodes of febrile neutropenia and temozolomide was generally well tolerated. In conclusion, temozolomide is an active therapy in patients with recurrent high grade glioma and our results concord with published studies.     

Chemotherapy of recurrent supratentorial malignant gliomas (phase II study)

At the Hungarian National Institute of Neurosurgery 73 recurrent supratentorial malignant tumours were treated by chemotherapy during the last ten years. Chemotherapy was applied after postoperative radiotherapy but in some cases following reoperation only. All cases were clinically and by CT or MRI verified recurrences. Forty-three patients received BCNU-DBD (dibromodulcitol) treatment (23 anaplastic astrocytoma--AA, and 20 glioblastoma multiforme--GM): day 1. BCNU 150 mg/sq.m. in i.v. infusion, day 2. dibromdulcitol 1000 mg/sq orally was given. This course was repeated every six weeks, altogether 2-8 times. Sixteen patients with AA responded with complete or partial regression but only 6 did with GM. Median survival was 14 and 7 months, the difference proved to be significant, p = 0.0091. PCV combination (procarbazine, CCNU, vincristine) was applied to 16 patients with AA and 14 cases with recurrent oligodendroglioma (O). Treatment started with vincristine 1.5 mg/sq.m. i.v. (2.0 mg maximum), the next day CCNU 100 mg/sq.m. was given, followed by procarbazine 60 mg/sq.m. on days 8-22. and finished by the same dose of vincristine on day 30. The course was repeated after one month, mostly six times. Six patients with AA did not respond; in cases of oligodendroglioma all but one responded with complete or partial improvement. It is remarkable that no significant difference was found between the survivals of BCNU-DBD or PCV treated AA patients. Chemotherapy of supratentorial malignant glioma recurrences with nitroso-ureas and their combination proved to be efficacious. It also seems, that in recurrent cases lower grade gliomas show better response rate than glioblastomas.     

立体定向放疗与常规放疗结合治疗高分级脑胶质瘤

目的采用立体定向放疗与常规放疗结合治疗高分级脑胶质瘤,分析其疗效,探讨其影响预后的因素.方法自1998年12月至2005年1月用立体定向放疗与常规放疗结合的方法治疗高分级脑胶质瘤106例.立体定向放疗针对GTV追加剂量,每次5～7Gy,共计5～7次,常规放疗主要针对亚临床病变,一般剂量为50Gy.寿命表法统计生存率.结果本组病例1、3年生存率分别为66.2%和27.0%.Ⅲ级胶质瘤较Ⅳ级的患者预后好,预后与年龄、肿瘤部位和治疗剂量等其他因素无关.结论立体定向放疗加常规放疗治疗高分级脑胶质瘤既发挥了放射物理剂量分布的优点,又符合放射生物学原则,较以往治疗提高了患者的生存机会.     

Rechallenge with temozolomide in recurrent glioma

Despite a confirmed survival benefit associated with adjuvant radio- and chemotherapy, the majority of patients with malignant glioma relapse after initial therapy. Recurrent malignant glioma treatment has not been standardised and usually the response rate to standard chemotherapy protocols for recurrent malignant glioma is less than 30%. The growing body of evidence demonstrating the clinical importance of O6-methylguanine methyltransferase (MGMT) has generated a considerable interest in the exploration of strategies to overcome MGMT-mediated resistance to alkylating agents; for example protracted administration of Temozolomide (TMZ) may result in more extensive and sustained depletion of MGMT; for this reason a variety of dosing schedules that increase the duration of exposure and the cumulative dose of TMZ are being investigated for the treatment of patient with recurrent malignant glioma after standard treatment. The most widely studied regimens in this setting include (1) 21 of 28-day schedule at a dose of 75-100 mg/m(2)/day; (2) 7 of 14-day schedule at a dose of 150 mg/m(2)/day, also referred to as the 'one week on/one week off' schedule; (3) Continuous daily schedule at a dose of 50 mg/m(2)/day. An alternative dosing schedule of TMZ may be a reasonable option in patients having high-grade gliomas with recurrence after standard therapy.