Combination celecoxib and temozolomide in C6 rat glioma orthotopic model

The purpose of this study was to determine whether a combination treatment of temozolomide with celecoxib is effective in the rat orthotopic glioma model. After stereotactic injection of C6/LacZ rat glioma cells into the Sprague Dawley rat brain, the rats were randomly assigned to four treatment groups [group 1, control treatment; group 2, celecoxib (25 mg/kg p.o. everyday) alone; group 3, temozolomide (7.5 mg/kg i.p. for 5 days at 2nd week) alone; group 4, a combination of celecoxib and temozolomide]. Rats were sacrificed 18 days after treatment, and the body weight, tumor volume, tumor cell proliferation, microvessel densities, and apoptosis were evaluated. There was a significant reduction of tumor volume in combination group compared to control or single-agent therapy. The median tumor volume was estimated to be 111.5 mm(3) (control), 65.0 mm(3) (celecoxib), 71.8 mm(3) (temozolomide) and 18.7 mm(3) (combination). In the combination group, there was increased tumor cell apoptosis as well as decreased microvessel density and tumor cell proliferation relative to the control and single-agent therapy (P<0.05). Collectively, the data suggest that the combination celecoxib and temozolomide may provide a novel and effective approach to the treatment of glioblastoma.     

Bevacizumab and dose-intense temozolomide in recurrent high-grade glioma

BackgroundAngiogenesis inhibition is a rational treatment strategy for high-grade glioma (HGG). Combined antiangiogenic therapy and chemotherapy could be beneficial, taking advantage of different mechanisms of antitumour activity of both therapies. We carried out a phase I–II clinical trial with the combination of bevacizumab and continuous dose-intense temozolomide (TMZ) for patients with a recurrent HGG after first- or second-line treatment.Patients and methodsTwenty-three HGG patients were treated with bevacizumab (10 mg/kg i.v. every 3 weeks) and TMZ (daily 50 mg/m²), until clinical or radiological progression. Conventional and dynamic magnetic resonance imaging (MRI) were carried out on days -4, 3 and 21 and until clinical or radiological progression.ResultsOverall response rate (20%), 6-month progression-free survival (PFS6) (17.4%), median progression-free survival (13.9 weeks) and median overall survival (OS) (17.1 weeks) were considerably lower compared with most other studies with bevacizumab-containing regimens. The dynamic MRI parameters contrast transfer coefficient and relative cerebral blood volume decreased rapidly during the early phases of treatment, reflecting changes in vascularisation and vessel permeability but not in tumour activity. In addition, >50% of patients showed oedema reduction and a reduced shift on T1 images.ConclusionTreatment with bevacizumab and TMZ is feasible and well tolerated but did not improve PFS6 and median OS.     

Treatment-related myelodysplastic syndrome after temozolomide for recurrent high-grade glioma

In patients with recurrent malignant glioma, treatment-related myelodysplastic syndrome (t-MDS) and acute leukemia are rare adverse effects because the median survival after relapse is limited. We report a 44-year-old woman with t-MDS (refractory anemia with excess blasts) following treatment of recurrent anaplastic astrocytoma with temozolomide (TMZ). A cytogenetic study showed del (3)(q11.1). MDS was diagnosed 8.4 months after beginning TMZ. The disease rapidly evolved into acute leukemia within 1 month after the onset of MDS, and the patient died 1 month later during induction chemotherapy. The prognosis of t-MDS is generally poor. Considering the increasing use of TMZ, which is regarded as a drug with moderate toxicity, careful follow-up with routine blood testing is vital.     

Multicentre CRC phase II trial of temozolomide in recurrent or progressive high-grade glioma

Purpose: Patients with progressive or recurrent supratentorial high-grade gliomas were entered into a multicentre phase II trial to evaluate the efficacy and toxicity of temozolomide. Methods: The treatment schedule was 150–200 mg/m² per day orally for 5 days repeated every 28 days. Response evaluation was by a combination of neurological status evaluation (MRC scale) and imaging. Results: Of 103 eligible patients enrolled, 11 (11%) achieved an objective response and a further 48 (47%) had stable disease. The median response duration was 4.6 months. Response rates were similar for anaplastic astrocytomas (grade III) and glioblastoma multiforme (grade IV) tumours. Predictable myelosuppression was the major toxicity. Conclusions: The observation of objective responses and tolerable side effects in this heterogeneous population of patients supports the further investigation of this agent in high-grade gliomas. Received: 24 October 1996 / Accepted 5 February 1997     

Efficacy of protracted dose-dense temozolomide in patients with recurrent high-grade glioma

The current standard therapy for newly diagnosed glioblastoma is multimodal, comprising surgical resection plus radiotherapy and concurrent temozolomide, then adjuvant temozolomide for 6 months. This has been shown to provide survival benefits; however, the prognosis for these patients remains poor, and most relapse. The objective of this prospective Phase II study was to evaluate the efficacy and tolerability of protracted, dose-dense temozolomide therapy (100 mg/m² for 21 consecutive days of a 28-day cycle) in patients with recurrent glioblastoma or grade 3 gliomas who had previously received standard therapy. Of the 25 patients included (median age 50 years), 20 were evaluable for radiologic response. Two patients had partial responses and 10 had stable disease (60% overall clinical benefit); 8 patients (40%) progressed after the first treatment cycle. Five patients were not assessed for radiologic response due to early clinical progression but were included in the progression-free survival (PFS) and overall survival (OS) analyses. The median follow-up time was 7 months (range, 1–14 months). The median PFS was 3 months (95% confidence interval, CI, 1.8–4.2) and the median OS was 7 months (95% CI 5.1–8.9). The 6-month PFS rate (primary endpoint) was 17.3% (95% CI 1.7–32.2) and the 1-year OS rate was 12% (95% CI −1–25). This regimen was well tolerated. The most frequent adverse event was lymphopenia (grade 3–4 in 20 patients); no opportunistic infections were reported. Treatment was discontinued due to toxicity in 2 patients (grade 4 hepatic toxicity and thrombocytopenia). These data suggest that protracted, dose-dense temozolomide had modest activity with manageable toxicity in patients with recurrent high-grade glioma previously treated with temozolomide.     

Phase II trial of temozolomide in children with recurrent high-grade glioma

SummaryPurpose The objective of the study was to evaluate the efficacy and toxicity of Temozolomide (TMZ) administered for 5 consecutive days in three daily dosing in children with recurrent or refractory high-grade glioma.Patients and methods Twenty-four patients with a median age of 10.5 years were enrolled onto this open-label, multicenter, phase II study. The patients were previously treated with surgical resection (17 of 24), radiotherapy (19 of 24) and chemotherapy (18 of 24). Therapy was administered orally three times a day for 5 consecutive days at the dose of 200 mg/m²/d×5 for chemotherapy naive patients. In patients heavily pretreated with chemotherapy the starting dose was of 150 mg/m²/d×5.Results A total of 95 cycles were administered. The median progression free-survival (PFS) was 3 months for the entire group while disease stabilization was obtained in 7 patients (29.1%), all with supratentorial tumors. No CR or PR was observed. TMZ treatment showed a limited toxicity. Thrombocytopenia was the most common hematological adverse effect.Our data suggest a marginal activity of TMZ in children with recurrent high-grade glioma.     

Phase II study of 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine chemotherapy with radiotherapy for treating malignant glioma in children

We conducted a single-arm phase II study to evaluate the efficacy and safety of radiotherapy combined with 6-thioguanine, procarbazine, dibromodulcitol, lomustine, and vincristine (TPDCV) chemotherapy for treating malignant astrocytoma in children and anaplastic ependymoma in patients of all ages. Between 1984 and 1992, 42 patients who had malignant astrocytomas (glioblastomas multiforme, anaplastic astrocytomas, or mixed anaplastic oligoastrocytomas) were treated with TPDCV chemotherapy and radiation therapy. Of these patients, 40 were younger than 18 years, but 2 were older (22 and 23 years) when treated. Cranial radiation averaged 58 Gy. TPDCV chemotherapy was given for 1 year or until progression. Between 1989 and 1991, 17 patients with malignant ependymoma were treated with TPDCV chemotherapy and craniospinal radiation. Radiation was given at an average dose of 54 Gy to the tumor, 28 Gy to the whole brain, and 31 Gy to the spinal axis. TPDCV chemotherapy was given for 1 year or until tumor progressed. Of the patients with glioblastoma multiforme, 13 of 17 died; the median time to progression was 49 weeks, and median survival was 85 weeks. The four patients surviving at this writing were followed a median 537 weeks (range 364-635 weeks). Of the patients with nonglioblastoma malignant astrocytoma, 14 of 25 died; the median time to progression was 224 weeks. Median survival was not reached in this group. The median follow-up for those surviving was 494 weeks. For the patients with ependymoma, 11 of 17 died with a median time to progression of 141 weeks. The median follow-up for the eight who survive was 469 weeks. Nine patients died with a median survival of 183 weeks. The combination of TPDCV and radiotherapy has activity against childhood anaplastic astrocytoma, glioblastoma multiforme, and anaplastic ependymoma. The results of this study for children with glioblastoma were comparable to results in the literature, while the results for children with anaplastic astrocytoma appeared better than most reports. The combination of TPDCV chemotherapy and radiation therapy for anaplastic ependymomas appears to be active and at least as good as published reports using radiation therapy alone.     

鸦胆子油乳联合阿帕替尼及替莫唑胺治疗复发性恶性脑胶质瘤

目的 探讨鸦胆子油乳联合阿帕替尼及替莫唑胺治疗复发性恶性脑胶质瘤患者的临床疗效、免疫功能影响及不良反应.方法 选取2016年6月至2018年12月期间郑州大学第一附属医院复发性恶性脑胶质瘤患者52例,随机分为2组,A组26例应用阿帕替尼及替莫唑胺治疗,B组26例应用鸦胆子油乳联合阿帕替尼及替莫唑胺治疗,比较2组临床疗效...     

Phase I trial of temozolomide plus O6-benzylguanine for patients with recurrent or progressive malignant glioma.

PURPOSE: We conducted a two-phase clinical trial in patients with progressive malignant glioma (MG). The first phase of this trial was designed to determine the dose of O6-BG effective in producing complete depletion of tumor AGT activity for 48 hours. The second phase of the trial was designed to define the maximum tolerated dose (MTD) of a single dose of temozolomide when combined with O6-BG. In addition, plasma concentrations of O6-BG and O6-benzyl-8-oxoguanine were evaluated after O6-BG. PATIENTS AND METHODS: For our first phase of the clinical trial, patients were scheduled to undergo craniotomy for AGT determination after receiving a 1-hour O6-BG infusion at 120 mg/m2 followed by a continuous infusion at an initial dose of 30 mg/m2/d for 48 hours. The dose of the continuous infusion of O6-BG escalated until tumor AGT was depleted. Once the O6-BG dose was established a separate group of patients was enrolled in the second phase of clinical trial, in which temozolomide, administered as a single dose at the end of the 1-hour O6-BG infusion, was escalated until the MTD was determined. RESULTS: The O6-BG dose found to be effective in depleting tumor AGT activity at 48 hours was an IV bolus of 120 mg/m2 over 1 hour followed by a continuous infusion of 30 mg/m2/d for 48 hours. On enrolling 38 patients in six dose levels of temozolomide, the MTD was established at 472 mg/m2 with dose-limiting toxicities limited to myelosuppression. CONCLUSION: This study provides the foundation for a phase II trial of O6-BG plus temozolomide in temozolomide-resistant MG.     

Continuous low-dose temozolomide and celecoxib in recurrent glioblastoma

Even after gross tumor resection and combined radiochemotherapy, glioblastomas recur within a few months. Salvage therapy often consists of rechallenging with temozolomide in a dose-intensified schedule. Previously, low-dose metronomic temozolomide in combination with cyclo-oxigenase 2 inhibitors has had a beneficial effect as first-line treatment for glioblastoma. We report our experience with this procedure in recurrent glioblastomas after standard treatment. From June 2007 to April 2009, 28 patients with recurrent glioblastoma received continuous low-dose temozolomide of 10 mg/m² twice daily and 200 mg celecoxib. Before therapy the recurrent tumor was resected in 19 of 28 patients. Microvessel density (MVD) was determined by immunohistochemistry in 19 patients, and MGMT promoter methylation status, using the pyrosequencing method, was determined in 17 patients. In 14/28 patients, positron emission tomography with [F-18]-fluoroethyl)-l-tyrosine (FET-PET) was performed. Tumor progression was defined by the Macdonald criteria on MRI every 8–12 weeks or by clinical deterioration. The median time to progression was 4.2 months. Progression-free survival (PFS) after 6 months was 43%. Except for a lymphopenia in one patient, there was no grade 3 or 4 toxicity. PFS did not correlate with MVD or MGMT status. A high FET uptake correlated with tumor control after 6 months under therapy (P = 0.041, t-test). Low-dose continuous temozolomide in combination with celecoxib seems to have activity in recurrent glioblastoma without relevant toxicity. High FET uptake correlated with a better outcome under metronomic therapy.     

Haematological malignancies following temozolomide treatment for paediatric high-grade glioma

BackgroundTemozolomide (TMZ) is widely used in high-grade glioma (HGG). There is a major concern of treatment-induced secondary haematological malignancies (SHMs). Due to the poor overall survival of HGG patients, the true incidence is yet elusive. Thus, the aim of this study was to determine the risk of SHMs following TMZ in paediatric HGG.MethodsWe analysed 487 patients from the HIT-HGG database of the German-speaking Society of Pediatric Oncology and Hematology with follow up beyond 1 year.ResultsThe incidence of SHM was 7.7 ± 3.2% at 10 years. No SHM occurred in 194 patients after first-line TMZ therapy, but four out of 131 patients treated with TMZ for relapse following first-line multiagent chemotherapy experienced SHM (20% at 10 years; p = 0.041). SHMs occurred in two out of 162 patients who underwent multiagent chemotherapy without TMZ (4.1% at 10 years). Gender, patient age and acute haematological toxicity during treatment did not affect the incidence of SHMs.ConclusionData of our cohort do not indicate an increased risk of SHM following TMZ treatment when compared to previous chemotherapy regimen. However, if TMZ is administered as a second-line treatment following conventional chemotherapy regimen, the risk might be disproportionately increasing.     

放疗联合替莫唑胺治疗术后高级别脑胶质瘤的临床分析

目的 评价放疗联合替莫唑胺(TMZ)治疗术后高级别胶质瘤的有效性和安全性,探讨影响预后的因素。方法 回顾分析2008—2015年间浙江省肿瘤医院收治的111例采用3DRT联合TMZ治疗初诊高级别胶质瘤术后患者的临床资料,观察疗效和安全性。Kaplan-Meier法计算生存率并Logrank法检验,Cox模型多因素预后分析。结果 1、2、3年样本数分别为71 、49、31例,OS率和PFS率分别为83.5%、46.9%、35.6%和52.2%、34.7%、26.4%。放化疗期间常见不良反应为急性中枢神经系统、血液学、肝及胃肠道反应,但多数均能耐受。病理分级是影响OS、PFS率的因素(P=0.000、0.000)。结论 3DRT联合TMZ治疗术后高级别胶质瘤疗效肯定,安全性较好。病理分级是影响患者预后的独立因素。     

贝伐单抗联合替莫唑胺治疗复发性脑胶质瘤的初步研究

目的　观察贝伐单抗联合替莫唑胺治疗复发性脑胶质瘤患者的近期疗效和安全性。方法　２０１０年２月至２０１０年９月共１８例复发性脑胶质瘤患者给予贝伐单抗联合替莫唑胺方案治疗,具体方案为：替莫唑胺１５０～２００ｍｇ／（ｍ２·ｄ）,口服,ｄ１～ｄ５,２８ｄ为１个周期;贝伐单抗５ｍｇ／ｋｇ,每１４ｄ静脉滴注１次。至少接受２个周期化疗后评价疗效和不良反应,并记录６个月无进展生存率和６个月总生存率。结果　１８例患者获ＰＲ６例（３３.３％）,ＳＤ９例（５０.０％）,ＰＤ３例（１６.７％）。６个月无进展生存率和总生存率分别为６６.７％（１２／１８）和７７.８％（１４／１８）。主要不良反应包括骨髓抑制和胃肠道反应,均为１～２级。结论　贝伐单抗联合替莫唑胺治疗复发性脑胶质瘤近期疗效较好,不良反应可耐受,远期疗效尚需进一步观察。     

羟基喜树碱与替莫唑胺治疗复发性高级别脑胶质瘤疗效比较

为了探讨羟基喜树碱(HCPT)和替莫唑胺(TMZ)治疗复发性高级别脑胶质瘤的疗效和毒副反应,将47例复发性高级别脑胶质瘤患者随机分为HCPT组23例和TMZ组24例,HCPT组给予HCPT 6 mg/(m2·d) 静脉滴入,连用7 d,每28 d重复;TMZ组给予TMZ胶囊150 mg/(m2·d) 口服,连用5 d,每28 d重复. HCPT组23例患者PR 5例,SD 9例,PD 9例,客观有效率(RR)为21.7%,临床受益率(CBR)为60.9%;TMZ组24例患者PR 6例,SD 9例,PD 8例,RR为26.1%,CBR为65.2%.两组TMZ和CBR比较,差异均无统计学意义,P＞0.05.HCPT组中位PFS为3.5个月,OS为7.8个月;TMZ组PFS和OS分别为4.1和8.3个月.两组半年无进展生存率分别为39.1%(9/23)和43.5%(10/23),半年总生存率为60.9%(14/23)和65.2%(15/23),两组比较差异无统计学意义,P>0.05.初步研究结果提示,HCPT单药治疗复发性高级别脑胶质瘤疗效与TMZ相近,是TMZ之外又一个安全有效的高级别脑胶质瘤化疗方案.     

Durable response of a radiation-induced,high-grade cerebellar glioma to temozolomide

Summary Background Radiation-induced high-grade gliomas are a rare but serious late complication of radiotherapy. We report a patient with radiation-induced cerebellar high-grade glioma who had a durable response to temozolomide. Patients and Methods Case report of a 77-year-old woman with a radiation-induced, high-grade cerebellar glioma that responded durably to temozolomide. Results Our patient developed a cerebellar high-grade glioma 9 years after treatment for a stage IV (T4N0M0) supraglottic laryngeal squamous cell carcinoma with cisplatinum and fluorouracil chemotherapy, and subsequently focal head and neck radiotherapy. Patient was treated with radiation and concurrent temozolomide (only partially due to toxicity) and was stable for 1 year without further adjuvant treatment. Subsequently the tumor recurred and the patient had a dramatic and durable response to standard 5 day dosing of adjuvant temozolomide. Conclusion High-grade gliomas are a late complication of radiation to the central nervous system and may respond to chemotherapy.     

三维适形放射治疗联合替莫唑胺治疗高级别脑胶质瘤

目的观察三维适形放射治疗(three-dimensional conformal radiotherapy,3D-CRT)联合替莫唑胺(temozolomide,TMZ)治疗高级别脑胶质瘤(high-grade glioma,HGG)的临床疗效。方法 65例术后HGG随机分成TMZ联合3D-CRT组(治疗组)和单纯3D-CRT组(对照组)。治疗组35例(WHO分级Ⅲ级21例,Ⅳ级14例),对照组30例(Ⅲ级18例,Ⅳ级12例)。头颅适形放疗DT60 Gy/(30 f.42 d),治疗组同时每日服用TMZ 75 mg/m2,直到放疗结束。随后用TMZ辅助化疗6疗程,150～200 mg/(m2.d)×5天,每28天重复。对照组按照上述放疗方案进行。结果 治疗组:1、2、3年生存率分别为88.6%(31/35)、45.7%(16/35)、25.7%(9/35),中位生存期20月。对照组:1、2、3年生存率分别为43.3%(13/30)、16.7%(5/30)、6.7%(2/30),中位生存期12月。两组1、2、3年生存率及3年间总的生存率和中位生存期比较差异均有统计学意义(P<0.05)。两组血液学毒性和放射性脑损伤症状均可耐受。结论 与单纯3D-CRT比较,3D-CRT联合TMZ化疗提高了HGG的生存率。     

A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood

A phase I trial was conducted to determine the maximum tolerated dose (MTD) of temozolomide given in combination with lomustine in newly diagnosed pediatric patients with high-grade gliomas. Response was assessed following two courses of therapy at the MTD. Temozolomide was administered to cohorts of patients at doses of 100, 125, 160, or 200 mg/m(2) on days 1-5, along with 90 mg/m(2) lomustine on day 1. Two courses of lomustine/temozolomide were given prior to radiation therapy (RT) and up to six courses were administered afterward. Thirty-two patients were enrolled. Dose-limiting myelosuppression was seen in two of three patients enrolled at the 200 mg/m(2) dose level. One of 14 patients in the expanded MTD cohort (160 mg/m(2)) experienced dose-limiting thrombocytopenia. After two courses at the MTD, one patient with a 5-mm enhancing nodule postoperatively had a complete response, one patient with a large residual temporal lobe glioblastoma had a partial response, and eight patients had stable disease. Several patients developed transient radiographic worsening after completing RT. Median 1- and 2-year overall survivals at the MTD were 60% +/- 13% and 40% +/- 13% with a median of 17.6 months. Thirteen of 20 patients (65%) who underwent MRI scans within 6 months prior to death developed metastatic disease. In conclusion, when administered with 90 mg/m(2) lomustine on day 1, the MTD of temozolomide is 160 mg/m(2)/day x 5. Radiographic changes following RT make determination of early tumor progression difficult. Metastatic disease is common prior to death.