Bevacizumab in recurrent high-grade pediatric gliomas

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promise in treating recurrent adult high-grade glioma (HGG). However, there is very little data on recurrent or progressive pediatric HGG treated with bevacizumab. We report the results of a single institution experience using bevacizumab and irinotecan in children who relapsed or progressed following standard therapy. Twelve pediatric patients with recurrent or progressive HGG received bevacizumab at 10 mg/kg every 2 weeks with irinotecan at 125 mg/m². Magnetic resonance imaging (MRI) was performed prior to therapy and every 8 weeks subsequently. Ten patients had supratentorial HGG; 2 had DIPG. Radiological responses were defined according to MacDonald''s criteria. Progression-free survival (PFS), overall survival (OS), and toxicities were analyzed. Ten (83.3%) patients tolerated bevacizumab without serious toxicity. Therapy was discontinued in 1 patient because of anaphylaxis. Another patient developed grade III delayed wound healing and deep vein thrombosis. Two patients (16.7%) experienced a partial response after the first MRI. No complete radiographic responses were seen. Stable disease was noted in 4 (33.3%) patients. The median PFS and OS were 2.25 and 6.25 months, respectively. A diffuse invasive recurrence pattern was noted in 5 (45.5%) patients. Treatment tolerance, toxicity, and recurrence profiles were comparable to adult HGG patients treated with bevacizumab. However, the radiological response rate, response duration, and survival appeared inferior in pediatric patients. Genetic differences in pediatric gliomas might account for this difference.     

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.     

Single dose versus fractionated stereotactic radiotherapy for recurrent high-grade gliomas

Purpose: To evaluate the efficacy of stereotactic radiotherapy (SRT) in patients with recurrent high-grade gliomas by comparing two different treatment regimens, single dose or fractionated radiotherapy.

Methods and Materials: Between April 1991 and January 1998, 71 patients with recurrent high-grade gliomas were treated with SRT. Forty-six patients (65%) were treated with single dose radiosurgery (SRS) and 25 patients (35%) with fractionated stereotactic radiotherapy (FSRT). For the SRS group, the median radiosurgical dose of 17 Gy was delivered to the median of 50% isodose surface (IDS) encompassing the target. For the FSRT group, the median dose of 37.5 Gy in 15 fractions was delivered to the median of 85% IDS.

Results: Actuarial median survival time was 11 months for the SRS group and 12 months for the FSRT group (p = 0.3, log-rank test). Variables predicting longer survival were younger age (p = 0.006), lower grade (p = 0.0006), higher Karnofsky Performance Scale (KPS) (p = 0.0005), and smaller tumor volume (p = 0.02). Patients in the SRS group had more favorable prognostic factors, with median age of 48 years, KPS of 70, and tumor volume of 10 ml versus median age of 53 years, KPS of 60, and tumor volume of 25 ml in the FSRT group. Late complications developed in 14 patients in the SRS group and 2 patients in the FSRT group (p < 0.05).

Conclusion: Given that FSRT patients had comparable survival to SRS patients, despite having poorer pretreatment prognostic factors and a lower risk of late complications, FSRT may be a better option for patients with larger tumors or tumors in eloquent structures. Since this is a nonrandomized study, further investigation is needed to confirm this and to determine an optimal dose/fractionation scheme.     

5-Aminolevulinic acid fluorescence guided surgery for recurrent high-grade gliomas

Journal of Neuro-Oncology - Fluorescence guided surgery (FGS) with five-aminolevulinic acid (5-ALA) is expected to revolutionize neurosurgical care of patients with high-grade gliomas (HGG). After...     

Reirradiation with concurrent bevacizumab for recurrent high-grade gliomas in adult patients

Purpose

To analyse feasibility, prognostic factors and patterns of recurrence after concurrent reirradiation and bevacizumab for recurrent high-grade gliomas.

Dose-dense temozolomide for recurrent high-grade gliomas: a single-center retrospective study

There are limited treatment modalities after high-grade gliomas recurrence. MGMT depletion modulated by dose-dense temozolomide (ddTMZ) remains a debated therapy for initial TMZ responders. Patients were selected retrospectively from our practice with diagnosis of high-grade gliomas (WHO grade III or IV), and were followed since the start of ddTMZ until death or change of therapy. Twenty-one patients were reviewed, with a median age of 47 (25–61) years and a median of 5.8 (1.5–38.8) cycles of ddTMZ. The majority were males (71.4%). Sixty-six percent received 21 on/28 off ddTMZ schedule, 28.6% daily, and 1 patient received a 7 days on/7 days off schedule. IDH mutation status was available for 18 (85.7%) patients, with 7 (33.3%) IDH mutant and 11 (52.5%) IDH wild type. MGMT methylation was assessed in 6 (28.6%) of the patients, being MGMT methylated in 3 (14.3%) patients, and non-methylated in 3 (14.3%) patients. The majority of patients (57.1%) were receiving ddTMZ in addition to other forms of therapy, including either bevacizumab (38.1%) or tumor-treating fields (TTFields) (19.1%). Overall ddTMZ was well tolerated, with few adverse events reported. The estimated median overall survival after ddTMZ start was 11 months. Median progression-free survival (PFS) was 6 months. Outcomes did not vary between patients receiving ddTMZ alone or those using TTFields or bevacizumab as concomitant therapy, but there was a trend to longer survival with the use of concomitant TTFields. Our results demonstrate benefit of ddTMZ after previous treatment with standard TMZ dosing with no apparent increase in treatment-related toxicities. In summary, ddTMZ should be considered in TMZ responsive patients and warrants further investigation.     

Targeting Wee1 for the treatment of pediatric high-grade gliomas

Background

We investigated the efficacy of the Wee1 inhibitor MK-1775 in combination with radiation for the treatment of pediatric high-grade gliomas (HGGs), including diffuse intrinsic pontine gliomas (DIPGs).

Methods

Gene expression analysis was performed for 38 primary pediatric gliomas (3 grade I, 10 grade II, 11 grade III, 14 grade IV) and 8 normal brain samples using the Agilent 4 × 44 K array. Clonogenic survival assays were carried out in pediatric and adult HGG cell lines (n = 6) to assess radiosensitizing effects of MK-1775. DNA repair capacity was evaluated by measuring protein levels of γ-H2AX, a marker of double strand DNA breaks. In vivo activity of MK-1775 with radiation was assessed in 2 distinct orthotopic engraftment models of pediatric HGG, including 1 derived from a genetically engineered mouse carrying a BRAF^V600E mutation, and 1 xenograft model in which tumor cells were derived from a patient''s DIPG.

Results

Wee1 is overexpressed in pediatric HGGs, with increasing expression positively correlated with malignancy (P = .007 for grade III + IV vs I + II) and markedly high expression in DIPG. Combination treatment of MK-1775 and radiation reduced clonogenic survival and increased expression of γ-H2AX to a greater extent than achieved by radiation alone. Finally, combined MK-1775 and radiation conferred greater survival benefit to mice bearing engrafted, orthotopic HGG and DIPG tumors, compared with treatment with radiation alone (BRAF^V600E model P = .0061 and DIPG brainstem model P = .0163).

Conclusion

Our results highlight MK-1775 as a promising new therapeutic agent for use in combination with radiation for the treatment of pediatric HGGs, including DIPG.     

Multi-institutional phase II study of temozolomide administered twice daily in the treatment of recurrent high-grade gliomas

BACKGROUND: The prognosis for patients with recurrent high-grade gliomas is poor and treatment options are limited. Current chemotherapeutic regimens can improve clinical outcomes, but extend survival by only a few months. Temozolomide is a methylating agent that is typically administered once daily. Because preclinical studies suggested that a twice-daily dosing schedule might be more effective, the safety and efficacy of twice-daily dosing of temozolomide were studied in patients with recurrent gliomas at their first, second, or third recurrence. METHODS: This multi-institutional trial enrolled 120 patients with recurrent glioblastoma multiforme (GBM), anaplastic astrocytoma (AA), or anaplastic oligodendroglioma (AO). An initial oral dose of 200 mg/m(2) of temozolomide was followed by 9 consecutive doses of 90-mg/m(2) every 12 hours. Treatment cycles were repeated every 28 days. Doses were escalated to 100 mg/m(2) twice daily in the absence of unacceptable toxicity or were reduced if unacceptable toxicity occurred. RESULTS: For GBM, AA, and AO patients, respectively, the median progression-free survival (PFS) was 4.2 months, 5.8 months, and 7.7 months, whereas the median overall survival (OS) was 8.8 months, 14.6 months, and 18 months. The overall response rate (partial and complete) for the GBM, AA, and AO patients was 31%, 46%, and 46%, respectively. Grade 3/4 toxicities included neutropenia (1.1%), thrombocytopenia (3.6%), and anemia (0.3%) (graded according to the World Health Organization grading system). CONCLUSIONS: Twice-daily dosing may enhance the efficacy of temozolomide in the treatment of recurrent gliomas without increasing toxicity. This regimen compares favorably with other dosing schedules of temozolomide reported in the literature.     

转移及复发性骨肿瘤的放射性125I粒子植入治疗初探

目的探讨放射性^125I粒子组织间种植治疗转移及复发性骨肿瘤的技术方法和疗效。方法对14例转移及复发性骨肿瘤患者行肿瘤内^125I粒子植入治疗，粒子植入数目为3～145颗，粒子活度为18．5～29．6MBq（0．5～0．8mCi），肿瘤匹配周边剂量为115～145Gy。术后行质量验证并观察患者临床指标改善情况。结果随访7～29个月（平均12．4个月）。^125I粒子治疗90％肿瘤靶体积接受的最小剂量（D90）中位值为108．12Gy（27～166Gy），10例脊柱或椎旁肿瘤患者脊髓的中位D90为31．9Gy（6．2～74．0Gy）。粒子植入前伴有疼痛的12例患者，术后疼痛完全缓解率达82％，止痛有效率为92％。10例脊柱或椎旁肿瘤患者中，70％的患者疗后行走能力改善或恢复正常。1年局部控制率为82％，1年生存率为53％，围手术期无3级以上严重并发症发生。结论放射性^125I粒子植入安全、高效，是治疗转移及复发性骨肿瘤的一种有前途的新方法。     

5-aminolevulinic acid photodynamic therapy for the treatment of high-grade gliomas

Journal of Neuro-Oncology - In the original article, the author names were published incorrectly. The names are correct in this publication.     

Stem cells as therapeutic vehicles for the treatment of high-grade gliomas

Stem cells have generated great interest in the past decade as potential tools for cell-based treatment of human high-grade gliomas. Thus far, 3 types of stem cells have been tested as vehicles for various therapeutic agents: embryonic, neural, and mesenchymal. The types of therapeutic approaches and/or agents examined in the context of stem cell-based delivery include cytokines, enzyme/prodrug suicide combinations, viral particles, matrix metalloproteinases, and antibodies. Each strategy has specific advantages and disadvantages. Irrespective of the source and/or type of stem cell, there are several areas of concern for their translation to the clinical setting, such as migration in the adult human brain, potential teratogenesis, immune rejection, and regulatory and ethical issues. Nonetheless, a clinical trial is under way using neural stem cell-based delivery of an enzyme/prodrug suicide combination for recurrent high-grade glioma. A proposed future direction could encompass the use of stem cells as vehicles for delivery of agents targeting glioma stem cells, which have been implicated in the resistance of high-grade glioma to treatment. Overall, stem cells are providing an unprecedented opportunity for cell-based approaches in the treatment of high-grade gliomas, which have a persistently dismal prognosis and mandate a continued search for therapeutic options.     

高分级脑胶质瘤术后放射治疗

放射治疗是高分级脑胶质瘤重要治疗手段之一,但疗效不理想,而术后适时放疗、精确勾画靶区,放疗总量＞60 Gy、适形调强放疗及联合化疗、靶向治疗是提高其放疗疗效的重要因素.     

Phase II trial of thalidomide and carmustine for patients with recurrent high-grade gliomas.

PURPOSE: The use of thalidomide as an antiangiogenic agent has met with only limited success in the treatment of malignant gliomas. On the basis of preclinical data demonstrating synergistic antitumor activity when antiangiogenic agents are combined with cytotoxic agents, we explored the clinical activity of the combination of thalidomide and carmustine (BCNU) in patients with recurrent high-grade gliomas. PATIENTS AND METHODS: Patients with a histologic diagnosis of high-grade glioma and radiographic evidence of tumor progression after standard surgery, radiation, and chemotherapy were eligible for the study. Patients received BCNU 200 mg/m2 on day 1 of every 6-week cycle, and 800 mg/d of thalidomide that was escalated to a maximal dose of 1,200 mg/d as tolerated. RESULTS: A total of 40 patients (38 with glioblastomas, two with anaplastic gliomas) were accrued to the study. The combination of thalidomide and BCNU was well tolerated; mild myelosuppression and mild to moderate sedation were the most common side effects. The median progression-free survival (100 days) and the objective radiographic response rate (24%) for patients with glioblastoma compared favorably with data from historical controls. CONCLUSION: This is one of the first clinical trials to evaluate the strategy of combining a putative antiangiogenic agent with a cytotoxic agent in patients with primary brain tumors. Our data demonstrate that thalidomide in combination with BCNU is well tolerated and has antitumor activity in patients with recurrent high-grade gliomas. Although the combination seems to be more active than either agent alone, such conclusions await confirmatory trials.     

Timing of re-irradiation in recurrent high-grade gliomas: a single institution study

There is no standard treatment available for recurrent high-grade gliomas. This monoinstitutional retrospective analysis evaluates the differences in overall survival and progression-free survival in patients according to the timing of re-irradiation. Patients suffering from a glioblastoma who received re-irradiation for recurrence were evaluated retrospectively. The median overall survival (OS) and the median progression-free survival were compared with different treatment options and within various time periods. From January 2007 until March 2015, 41 patients suffering from recurrent high-grade gliomas received re-irradiation [median dose of 30.6 Gy (range 20–40 Gy) in median 4 Gy fractions (range 1.8–5 Gy)] in our institution after initial postoperative irradiation or combined radiochemotherapy. The OS in this population was 34 months, and the OS after recurrence (OS-R) was 13 months. After diagnosis of recurrence, patients underwent additional surgical resection after a median of 1.2 months, received a second-line systemic therapy after 2.2 months with or without re-irradiation after 5.7 months. Growth of the tumour was assessed 4.3 months after the start of re-irradiation. The OS after the second surgical resection was 12.2 months, 11.7 months after the start of the second-line systemic therapy, and 6.7 months after the start of re-irradiation. The OS-R was not significantly correlated with the start of re-irradiation after a diagnosis of recurrence or the time period after the previous surgery. At this institution, re-irradiation was performed later compared to other treatment options. However, select patients could benefit from irradiation at an earlier time point. A precise time point should still be evaluated on an individual basis due to the patient’s diverse conditions.     

Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas

The North American Brain Tumor Consortium (NABTC) uses 6-month progression-free survival (6moPFS) as the efficacy end point of therapy trials for adult patients with recurrent high-grade gliomas. In this study, we investigated whether progression status at 6 months predicts survival from that time, implying the potential for prolonged survival if progression could be delayed. We also evaluated earlier time points to determine whether the time of progression assessment alters the strength of the prediction. Data were from 596 patient enrollments (159 with grade III gliomas and 437 with grade IV tumors) in NABTC phase II protocols between February 1998 and December 2002. Outcome was assessed statistically using Kaplan-Meier curves and Cox proportional hazards models. Median survivals were 39 and 30 weeks for patients with grade III and grade IV tumors, respectively. Twenty-eight percent of patients with grade III and 16% of patients with grade IV tumors had progression-free survival of >26 weeks. Progression status at 9, 18, and 26 weeks predicted survival from those times for patients with grade III or grade IV tumors (p < 0.001 and hazard ratios < 0.5 in all cases). Including KPS, age, number of prior chemotherapies, and response in a multivariate model did not substantively change the results. Progression status at 6 months is a strong predictor of survival, and 6moPFS is a valid end point for trials of therapy for recurrent malignant glioma. Earlier assessments of progression status also predicted survival and may be incorporated in the design of future clinical trials.     

Re-irradiation with and without bevacizumab as salvage therapy for recurrent or progressive high-grade gliomas

The optimal treatment for recurrent high-grade gliomas is unknown and a standard of care does not exist. Re-irradiation with concomitant bevacizumab represents an option. Retrospectively, we analyzed a cohort of heavily pretreated patients (n = 14) with relapsing HGGs who underwent re-irradiation with conventional 3D-conformal or intensified modulated radiotherapy (IMRT). Ten of them received re-irradiation in combination with bevacizumab. The study population consisted of eight GBMs and six anaplastic gliomas. All patients had previously undergone irradiation for first-line therapy, including seven patients with radiochemotherapy with temozolomide. Patients without contraindications started with two infusions of bevacizumab (10 mg/kg of body weight every other week) prior to re-irradiation and continued through re-irradiation until progression. The median patient age was 45 years with a median Karnofsky performance scale of 70. The median dose of re-irradiation was 41.6 Gy [39–55 Gy]. The median physical cumulative radiation dose was 101.6 Gy [65–110.4 Gy]. The median PFS from re-irradiation was 5.1 months [1.6–17.4] based on clinical and RANO criteria. Median OS from re-irradiation was 9.0 months [6.4–17.8]. We detected radionecrosis due to advanced imaging in one patient. Other toxicities were expected and attributable well known side effects of bevacizumab. This retrospective study provides additional feasibility and safety data of conventional 3D-conformal re-irradiation and IMRT in combination with bevacizumab in relapsing high-grade gliomas.     

Temozolomide and radiotherapy as first-line treatment of high-grade gliomas

AIMS AND BACKGROUND: Temozolomide, a novel alkylating agent, has shown promising results in the treatment of patients with high-grade gliomas, when used as single agent as well as in combination with radiation therapy. MATERIALS AND METHODS: In this report we retrospectively reviewed the clinical outcome of 128 consecutive patients with a diagnosis of high-grade gliomas referred to our Institutions from April 1994 to November 2001. The first 64 patients were treated with radiotherapy alone and the other 64 with a combination of radiotherapy and temozolomide (31 with radiotherapy and adjuvant temozolomide and 33 with radiotherapy and concomitant temozolomide followed by adjuvant temozolomide). RESULTS: Grade 3 hematological toxicity was scored in 9% of 64 patients treated with radiotherapy and temozolomide. No grade 4 hematological toxicity was reported, and the other acute side effects observed were mild or easily controlled with medications. Age, histology and administration of temozolomide were statistically significant prognostic factors associated with better 2-year overall survival. In contrast, we did not observe a significant difference in overall survival between adjuvant and concomitant/adjuvant temozolomide administration. CONCLUSIONS: We report the favorable results of a schedule combining radiotherapy and temozolomide in the treatment of patients with high-grade gliomas. The literature data and above all the findings of the phase III EORTC-NCIC 26981 trial suggest that actually the schedule can be used routinely in clinical practice. Further clinical studies, using temozolomide in combination with other agents, are required.